Administration of HCV protease inhibitors in combination with food to improve bioavailability

ABSTRACT

Methods of treating, preventing or ameliorating one or more symptoms of hepatitis C in a subject comprising the step of administering at least one HCV protease inhibitor in combination with food are provided. Also provided are methods of increasing bioavailability of an HCV protease inhibitor and methods of increasing serum levels of an HCV protease inhibitor in a subject. All methods comprise adminstering at least one HCV protease inhibitor in combination with food, the at least one HCV protease inhibitor selected from the group consisting of compounds of Formulae I-XXVI, described herein. Administration of compounds of the present invention in combination with food provides improved bioavailability and increased peak serum levels of the compounds as compared to administration without food.

CROSS REFERENCE TO PRIORITY APPLICATION

This application claims priority from U.S. provisional patentapplication Ser. No. 60/686,925 filed Jun. 2, 2005.

FIELD OF THE INVENTION

The present invention relates to administering compounds that are usefulfor treating a wide variety of diseases or disorders associated withhepatitis C virus (“HCV”) by inhibiting HCV protease (for example HCVNS3/NS4a serine protease), and/or diseases or disorders associated withcathepsin activity and inhibiting cathepsin activity. The compounds areadministered in combination with food to enhance absorption of thecompounds in the gastrointestinal tract and increase bioavailability ofthe compounds.

BACKGROUND OF THE INVENTION

HCV has been implicated in cirrhosis of the liver and in induction ofhepatocellular carcinoma. The prognosis for patients suffering from HCVinfection is currently poor. HCV infection is more difficult to treatthan other forms of hepatitis due to the lack of immunity or remissionassociated with HCV infection. Current data indicates a less than 50%survival rate at four years post cirrhosis diagnosis. Patients diagnosedwith localized resectable hepatocellular carcinoma have a five-yearsurvival rate of 10-30%, whereas those with localized unresectablehepatocellular carcinoma have a five-year survival rate of less than 1%.

Current therapies for hepatitis C include interferon-α (INF_(α)) andcombination therapy with ribavirin and interferon. See, e.g., Beremgueret al. (1998) Proc. Assoc. Am. Physicians 110(2):98-112. These therapiessuffer from a low sustained response rate and frequent side effects.See, e.g., Hoofnagle et al. (1997) N. Engl. J. Med. 336:347. Currently,no vaccine is available for HCV infection.

Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus thathas been implicated as the major causative agent in non-A, non-Bhepatitis (NANBH), particularly in blood-associated NANBH(BB-NANBH)(see, International Patent Application Publication No. WO89/04669 and European Patent Application Publication No. EP 381 216).NANBH is to be distinguished from other types of viral-induced liverdisease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), deltahepatitis virus (HDV), cytomegalovirus (CMV) and Epstein-Barr virus(EBV), as well as from other forms of liver disease such as alcoholismand primary biliar cirrhosis.

Recently, an HCV protease necessary for polypeptide processing and viralreplication has been identified, cloned and expressed; (see, e.g., U.S.Pat. No. 5,712,145). This approximately 3000 amino acid polyproteincontains, from the amino terminus to the carboxy terminus, anucleocapsid protein (C), envelope proteins (E1 and E2) and severalnon-structural proteins (NS1, 2, 3, 4a, 5a and 5b). NS3 is anapproximately 68 kda protein, encoded by approximately 1893 nucleotidesof the HCV genome, and has two distinct domains: (a) a serine proteasedomain consisting of approximately 200 of the N-terminal amino acids;and (b) an RNA-dependent ATPase domain at the C-terminus of the protein.The NS3 protease is considered a member of the chymotrypsin familybecause of similarities in protein sequence, overall three-dimensionalstructure and mechanism of catalysis. Other chymotrypsin-like enzymesare elastase, factor Xa, thrombin, trypsin, plasmin, urokinase, tPA andPSA. The HCV NS3 serine protease is responsible for proteolysis of thepolypeptide (polyprotein) at the NS3/NS4a, NS4a/NS4b, NS4b/NS5a andNS5a/NS5b junctions and is thus responsible for generating four viralproteins during viral replication. This has made the HCV NS3 serineprotease an attractive target for antiviral chemotherapy.

It has been determined that the NS4a protein, an approximately 6 kdapolypeptide, is a co-factor for the serine protease activity of NS3.Autocleavage of the NS3/NS4a junction by the NS3/NS4a serine proteaseoccurs intramolecularly (i.e., cis) while the other cleavage sites areprocessed intermolecularly (trans).

Analysis of the natural cleavage sites for HCV protease revealed thepresence of cysteine at P1 and serine at P1′ and that these residues arestrictly conserved in the NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions.The NS3/NS4a junction contains a threonine at P1 and a serine at P1′.The Cys→Thr substitution at NS3/NS4a is postulated to account for therequirement of cis rather than trans processing at this junction. See,e.g., Pizzi et al. (1994) Proc. Natl. Acad. Sci (USA) 91:888-892, Faillaet al. (1996) Folding & Design 1:35-42. The NS3/NS4a cleavage site isalso more tolerant of mutagenesis than the other sites. See, e.g.,Kollykhalov et al. (1994) J. Virol. 68:7525-7533. It has also been foundthat acidic residues in the region upstream of the cleavage site arerequired for efficient cleavage. See, e.g., Komoda et al. (1994) J.Virol. 68:7351-7357.

Inhibitors of HCV protease that have been reported include antioxidants(see, International Patent Application Publication No. WO 98/14181),certain peptides and peptide analogs (see, International PatentApplication Publication No. WO 98/17679, Landro et al. (1997) Biochem.36:9340-9348, Ingallinella et al. (1998) Biochem. 37:8906-8914,Llinàs-Brunet et al. (1998) Bioorg. Med. Chem. Lett. 8:1713-1718),inhibitors based on the 70-amino acid polypeptide eglin c (Martin et al.(1998) Biochem. 37:11459-11468, inhibitors affinity selected from humanpancreatic secretory trypsin inhibitor (hPST1-C3) and minibodyrepertoires (MBip) (Dimasi et al. (1997) J. Virol. 71:7461-7469),cV_(H)E2 (a “camelized” variable domain antibody fragment) (Martin etal. (1997) Protein Eng. 10:607-614), and α1-antichymotrypsin (ACT)(Elzouki et al.) (1997) J. Hepat. 27:42-28). A ribozyme designed toselectively destroy hepatitis C virus RNA has recently been disclosed(see, BioWorld Today 9(217): 4 (Nov. 10, 1998)).

Reference is also made to the PCT Publications, No. WO 98/17679,published Apr. 30, 1998 (Vertex Pharmaceuticals Incorporated); WO98/22496, published May 28, 1998 (F. Hoffmann-La Roche AG); and WO99/07734, published Feb. 18, 1999 (Boehringer Ingelheim Canada Ltd.).

Pending and copending U.S. patent applications, Ser. No. 60/194,607,filed Apr. 5, 2000, and Ser. No. 60/198,204, filed Apr. 19, 2000, Ser.No. 60/220,110, filed Jul. 21, 2000, Ser. No. 60/220,109, filed Jul. 21,2000, Ser. No. 60/220,107, filed Jul. 21, 2000, Ser. No. 60/254,869,filed Dec. 12, 2000, Ser. No. 60/220,101, filed Jul. 21, 2000, Ser. No.60/568,721 filed May 6, 2004, and WO 2003/062265, disclose various typesof peptides and/or other compounds as NS-3 serine protease inhibitors ofhepatitis C virus.

There is a need for new treatments and therapies for HCV infection totreat, prevent or ameliorate one or more symptoms of hepatitis C,methods for modulating the activity of serine proteases, particularlythe HCV NS3/NS4a serine protease, and methods of modulating theprocessing of the HCV polypeptide using the compounds provided herein.

Another aspect of the present invention is directed to inhibitingcathepsin activity. Cathepsins (Cats) belong to the papain superfamilyof lysosomal cysteine proteases. Cathepsins are involved in the normalproteolysis and turnover of target proteins and tissues as well as ininitiating proteolytic cascades by proenzyme activation and inparticipating in MHC class II molecule expression. Baldwin (1993) Proc.Natl. Acad. Sci., 90: 6796-6800; Mixuochi (1994) Immunol. Lett.,43:189-193.

However, aberrant cathepsin expression has also been implicated inseveral serious human disease states. Cathepsins have been shown to beabundantly expressed in cancer cells, including breast, lung, prostate,glioblastoma and head/neck cancer cells, (Kos et al. (1998) Oncol. Rep.,5:1349-1361; Yan et al. (1998) Biol. Chem., 379:113-123; Mort et al.(1997) Int. J Biochem. Cell Biol., 29: 715-720; Friedrick et al. (1999)Eur. J Cancer, 35:138-144) and are associated with poor treatmentoutcome of patients with breast cancer, lung cancer, brain tumor andhead/neck cancer. Kos et al, supra. Additionally, aberrant expression ofcathepsin is evident in several inflammatory disease states, includingrheumatoid arthritis and osteoarthritis. Keyszer (1995) ArthritisRheum., 38:976-984.

The molecular mechanisms of cathepsin activity are not completelyunderstood. Recently, it was shown that forced expression of cathepsin Brescued cells from serum deprivation-induced apoptotic death (Shibata etal. (1998) Biochem. Biophys. Res. Commun., 251: 199-203) and thattreatment of cells with antisense oligonucleotides of cathepsin Binduced apoptosis. Isahara et at. (1999) Neuroscience, 91:233-249. Thesereports suggest an anti-apoptotic role for the cathepsins that iscontrary to earlier reports that cathepsins are mediators of apoptosis.Roberts et al (1997) Gastroenterology, 113: 1714-1726; Jones et al.(1998) Am. J Physiol., 275: G723-730.

Cathepsin K is a member of the family of enzymes which are part of thepapain superfamily of cysteine proteases. Cathepsins B, H, L, N and Shave been described in the literature. Recently, cathepsin K polypeptideand the cDNA encoding such polypeptide were disclosed in U.S. Pat. No.5,501,969 (called cathepsin O therein). Cathepsin K has been recentlyexpressed, purified, and characterized. Bossard, M. J., et al., (1996) JBiol. Chem. 271, 12517-12524; Drake, F. H., et al., (1996) J. Biol.Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271,2126-2132.

Cathepsin K has been variously denoted as cathepsin O, cathepsin X orcathepsin O2 in the literature. The designation cathepsin K isconsidered to be the more appropriate one (name assigned by NomenclatureCommittee of the International Union of Biochemistry and MolecularBiology).

Cathepsins of the papain superfamily of cysteine proteases function inthe normal physiological process of protein degradation in animals,including humans, e.g., in the degradation of connective tissue.However, elevated levels of these enzymes in the body can result inpathological conditions leading to disease. Thus, cathepsins have beenimplicated in various disease states, including but not limited to,infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma bruceibrucei, and Crithidia fusiculata; as well as in schistosomiasis malaria,tumor metastasis, metachromatic leukodystrophy, muscular dystrophy,amytrophy, and the like. See International Publication Number WO94/04172, published on Mar. 3, 1994, and references cited therein. Seealso European Patent Application EP 0 603 873 A1, and references citedtherein. Two bacterial cysteine proteases from P. gingivallis, calledgingipains, have been implicated in the pathogenesis of gingivitis.Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2,445-458.

Cathepsin K is believed to play a causative role in diseases ofexcessive bone or cartilage loss. Bone is composed of a protein matrixin which spindle- or plate-shaped crystals of hydroxyapatite areincorporated. Type I Collagen represents the major structural protein ofbone comprising approximately 90% of the structural protein. Theremaining 10% of matrix is composed of a number of non-collagenousproteins, including osteocalcin, proteoglycans, osteopontin,osteonectin, thrombospondin, fibronectin, and bone sialoprotein.Skeletal bone undergoes remodeling at discrete foci throughout life.These foci, or remodeling units, undergo a cycle consisting of a boneresorption phase followed by a phase of bone replacement. Boneresorption is carried out by osteoclasts, which are multinuclear cellsof hematopoietic lineage. In several disease states, such asosteoporosis and Paget's disease, the normal balance between boneresorption and formation is disrupted, and there is a net loss of boneat each cycle. Ultimately, this leads to weakening of the bone and mayresult in increased fracture risk with minimal trauma.

The abundant selective expression of cathepsin K in osteoclasts stronglysuggests that this enzyme is essential for bone resorption. Thus,selective inhibition of cathepsin K may provide an effective treatmentfor diseases of excessive bone loss, including, but not limited to,osteoporosis, gingival diseases such as gingivitis and periodontitis,Paget's disease, hypercalcemia of malignancy, and metabolic bonedisease. Cathepsin K levels have also been demonstrated to be elevatedin chondroclasts of osteoarthritic synovium. Thus, selective inhibitionof cathepsin K may also be useful for treating diseases of excessivecartilage or matrix degradation, including, but not limited to,osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cellsalso typically express high levels of proteolytic enzymes that degradethe surrounding matrix. Thus, selective inhibition of cathepsin K mayalso be useful for treating certain neoplastic diseases.

There are reports in the literature of the expression of Cathepsin B andL antigen and that activity is associated with early colorectal cancerprogression. Troy et al., (2004) Eur J Cancer, 40(10):1610-6. Thefindings suggest that cysteine proteases play an important role incolorectal cancer progression.

Cathepsin L has been shown to be an important protein mediating themalignancy of gliomas and it has been suggested that its inhibition maydiminish their invasion and lead to increased tumor cell apoptosis byreducing apoptotic threshold. Levicar et al., (2003) Cancer Gene Ther.,10(2): 141-51.

Katunama et al., (2002) Arch Biochem Biophys., 397(2):305-11 reports onantihypercalcemic and antimetastatic effects of CLIK-148 in vivo, whichis a specific inhibitor of cathepsin L. This reference also reports thatCLIK-148 treatment reduced distant bone metastasis to the femur andtibia of melanoma A375 tumors implanted into the left ventricle of theheart.

Rousselet et al., (2004) Cancer Res., 64(1): 146-51 reports thatanti-cathepsin L single chain variable fragment (ScFv) could be used toinhibit the tumorigenic and metastatic phenotype of human melanoma,depending on procathepsin L secretion, and the possible use ofanti-cathepsin L ScFv as a molecular tool in a therapeutic cellularapproach.

Colella et al., (2003) Biotech Histochem., 78(2):101-8 reports that thecysteine proteinases cathepsin L and B participate in the invasiveability of the PC3 prostrate cancer cell line, and the potential ofusing cystein protease inhibitiors such as cystatins as anti-metastaticagents.

Krueger et al., (2001) Cancer Gene Ther., 8(7):522-8 reports that inhuman osteosarcoma cell line MNNG/HOS, cathepsin L influences cellularmalignancy by promoting migration and basement membrane degradation.

Frohlich et al., (2204) Arch Dermatol Res., 295(10):411-21 reports thatcathepsins B and L are involved in invasion of basal cell carcinoma(BCC) cells.

U.S. Provisional Patent application Ser. No. Not Yet Assigned, entitled“Compounds for Inhibiting Cathepsin Activity”, filed Apr. 20, 2005,discloses various types of peptides and/or other compounds as inhibitorsof cathepsin.

Cathepsins therefore are attractive targets for the discovery of novelchemotherapeutics and methods of treatment effective against a varietyof diseases. There is a need for compounds useful in the inhibition ofcathepsin activity and in the treatment of these disorders.

Gastro-intestinal absorption of an oral dose of medication is influencedby many factors in the gastrointestinal tract. Attributes of themembrane, pH, blood supply, transit time, and surface area determine theparticular location of absorption, such as the stomach, small intestineor large intestine. For example, the esophagus has a very thick membraneand virtually no absorption occurs while a drug is passing through theesophagus. The stomach has a thick mucous layer and the time that a drugresides there is usually relatively short, resulting in poor absorptiondespite the fact that it has a large epithelial surface. The smallintestine has a very large surface area, and absorption of virtually alldrugs is faster from the small intestine than from the stomach.Therefore, gastric emptying is a rate-limiting step in drug absorption.

It would be desirable to improve absorption, bioavailability and theeffects of the drug in a treatment regimen.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method of treating,preventing or ameliorating one or more symptoms of hepatitis C in asubject comprising the step of administering at least one compound offormulae I-XXVI in combination with food, wherein the at least onecompound is at least one compound of formulae I-XXVI set forth below.

In an additional aspect, the present invention provides a method ofincreasing bioavailability of a compound of formulae I-XXVI in a subjectcomprising administering at least one compound in combination with food,wherein the at least one compound is at least one compound of formulaeI-XXVI set forth below.

In a further aspect, the present invention provides a method ofincreasing the serum level of a compound in a subject comprisingadminstering the at least one compound in combination with food, whereinthe at least one compound is a compound of formulae I-XXVI set forthbelow.

In one embodiment, the compound is a compound of structural formula I:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

Y is selected from the group consisting of the following moieties:alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe optionallysubstituted with X¹¹ or X¹²;

X¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl, with the proviso that X¹¹ may beadditionally optionally substituted with X¹²;

X¹² is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²;

R¹ is COR⁵, wherein R⁵ is COR⁷ wherein R⁷ is NHR⁹, wherein R⁹ isselected from the group consisting of H, alkyl, aryl, heteroalkyl,heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl,

[CH(R^(1′))]_(p)COOR¹¹, [CH(R^(1′))]_(p)CONR¹²R¹³,[CH(R^(1′))]_(p)SO₂R¹¹, [CH(R^(1′))]_(p)COR¹¹,[CH(R^(1′))]_(p)CH(OH)R¹¹, CH(R^(1′))CONHCH(R²)COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONR¹²R¹³, CH(R^(1′))CONHCH(R²)R′,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))COOR¹¹andCH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))CONR¹²R¹³,wherein R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), R¹¹, R¹², R¹³, and R′are independently selected from the group consisting of H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl,aryl-alkyl and heteroaralkyl;

Z is selected from O, N, CH or CR;

W maybe present or absent, and if W is present, W is selected from C═O,C═S, C(═N—CN), or SO₂;

Q maybe present or absent, and when Q is present, Q is CH, N, P,(CH₂)_(p), (CHR)_(p), (CRR′)_(p), O, NR, S, or SO₂; and when Q isabsent, M may be present or absent; when Q and M are absent, A isdirectly linked to L;

A is O, CH₂, (CHR)_(p), (CHR—CHR′)_(p), (CRR′)_(p), NR, S, SO₂ or abond;

E is CH, N, CR, or a double bond towards A, L or G;

G may be present or absent, and when G is present, G is (CH₂)_(p),(CHR)_(p), or (CRR′)_(p); and when G is absent, J is present and E isdirectly connected to the carbon atom in Formula I as G is linked to;

J maybe present or absent, and when J is present, J is (CH₂)_(p),(CHR)_(p), or (CRR′)_(p), SO₂, NH, NR or O; and when J is absent, G ispresent and E is directly linked to N shown in Formula I as linked to J;

L may be present or absent, and when L is present, L is CH, CR, O, S orNR; and when L is absent, then M may be present or absent; and if M ispresent with L being absent, then M is directly and independently linkedto E, and J is directly and independently linked to E;

M may be present or absent, and when M is present, M is O, NR, S, SO₂,(CH₂)_(p), (CHR)_(p)(CHR—CHR′)_(p), or (CRR′) p;

p is a number from 0 to 6; and

R, R′, R², R³ and R⁴ are independently selected from the groupconsisting of H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₃-C₈ cycloalkyl; C₃-C₈heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido,ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein saidcycloalkyl is made of three to eight carbon atoms, and zero to sixoxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of oneto six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;

wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionallyand chemically-suitably substituted, with said term “substituted”referring to optional and chemically-suitable substitution with one ormore moieties selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy,thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester,carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, andhydroxamate;

further wherein said unit N—C-G-E-L-J-N represents a five-membered orsix-membered cyclic ring structure with the proviso that when said unitN—C-G-E-L-J-N represents a five-membered cyclic ring structure, or whenthe bicyclic ring structure in Formula I comprising N, C, G, E, L, J, N,A, Q, and M represents a five-membered cyclic ring structure, then saidfive-membered cyclic ring structure lacks a carbonyl group as part ofthe cyclic ring.

In another embodiment, the “at least one compound” is a compound offormula: II:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

Z is NH;

X is alkylsulfonyl, heterocyclylsulfonyl, heterocyclylalkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, heterocyclylcarbonyl,heterocyclylalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, alkyaminocarbonyl, heterocyclylaminocarbonyl,arylaminocarbonyl, or heteroarylaminocarbonyl moiety, with the provisothat X may be additionally optionally substituted with R¹² or R¹³;

X¹ is H; C₁-C₄ straight chain alkyl; C₁-C₄ branched alkyl or; CH₂-aryl(substituted or unsubstituted);

R¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl moiety, with the proviso that R¹²may be additionally optionally substituted with R¹³.

R¹³ is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitromoiety, with the proviso that the alkyl, alkoxy, and aryl may beadditionally optionally substituted with moieties independently selectedfrom R¹³.

P1a, P1b, P2, P3, P4, P5, and P6 are independently: H; C1-C10 straightor branched chain alkyl; C2-C10 straight or branched chain alkenyl;C3-C8 cycloalkyl, C3-C8 heterocyclic; (cycloalkyl)alkyl or(heterocyclyl)alkyl, wherein said cycloalkyl is made up of 3 to 8 carbonatoms, and zero to 6 oxygen, nitrogen, sulfur, or phosphorus atoms, andsaid alkyl is of 1 to 6 carbon atoms; aryl, heteroaryl, arylalkyl, orheteroarylalkyl, wherein said alkyl is of 1 to 6 carbon atoms;

wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl; (cycloalkyl)alkyland (heterocyclyl)alkyl moieties may be optionally substituted with R¹³,and further wherein said P1a and P1b may optionally be joined to eachother to form a spirocyclic or spiroheterocyclic ring, with saidspirocyclic or spiroheterocyclic ring containing zero to six oxygen,nitrogen, sulfur, or phosphorus atoms, and may be additionallyoptionally substituted with R¹³; and

P1′ is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclyl-alkyl, aryl, aryl-alkyl, heteroaryl, orheteroaryl-alkyl; with the proviso that said P1′ may be additionallyoptionally substituted with R¹³.

In another embodiment, the “at least one compound” is a compound offormula III:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

G is carbonyl;

J and Y may be the same or different and are independently selected fromthe group consisting of the moieties: H, alkyl, alkyl-aryl, heteroalkyl,heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy,alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy,cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino and heterocycloalkylamino, with theproviso that Y maybe additionally optionally substituted with X¹¹ orX¹²;

X¹¹ is selected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl,alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkylmoiety, with the proviso that X¹¹ may be additionally optionallysubstituted with X¹²;

X¹² is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²;

R¹ is COR⁵ or C(OR)₂, wherein R⁵ is selected from the group consistingof H, OH, OR⁸, NR⁹R¹⁰, CF₃, C₂F₅, C₃F₇, CF₂R⁶, R⁶ and COR⁷ wherein R⁷ isselected from the group consisting of H, OH, OR⁸, CHR⁹R¹⁰, and NR⁹R¹⁰,wherein R⁶, R⁸, R⁹ and R¹⁰ may be the same or different and areindependently selected from the group consisting of H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl,heteroarylalkyl, CH(R^(1′))COOR¹¹, CH(R^(1′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))COOR¹¹, CH(R^(1′))CONHCH(R^(2′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))R′,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))COOR¹¹,andCH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))CONR¹²R¹³,wherein R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), R¹¹, R¹², R¹³, and R′may be the same or different and are independently selected from a groupconsisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl,alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl;

Z is selected from O, N, or CH;

W maybe present or absent, and if W is present, W is selected from C═O,C═S, or SO₂; and

R, R′, R², R³ and R⁴ are independently selected from the groupconsisting of H; C1-C10 alkyl; C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido,ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro;oxygen, nitrogen, sulfur, or phosphorus atoms (with said oxygen,nitrogen, sulfur, or phosphorus atoms numbering zero to six);(cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkylis made of three to eight carbon atoms, and zero to six oxygen,nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to sixcarbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;

wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionallysubstituted, with said term “substituted” referring to optional andchemically-suitable substitution with one or more moieties selected fromthe group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl,cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy,alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate,urea, ketone, aldehyde, cyano, nitro, sulfonamide, sulfoxide, sulfone,sulfonylurea, hydrazide, and hydroxamate.In another embodiment, the inhibitor is a compound of Formula IV

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:Y is selected from the group consisting of the following moieties:alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe optionallysubstituted with X¹¹ or X¹²;X¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl, with the proviso that X¹¹ may beadditionally optionally substituted with X¹²;X¹² is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²;

R¹ is selected from the following structures:

wherein k is a number from 0 to 5, which can be the same or different,R¹¹ denotes optional substituents, with each of said substituents beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, cycloalkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino,heterocycloalkylamino, hydroxy, thio, alkylthio, arylthio, amino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido,carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, and nitro,with the proviso that R¹¹ (when R¹¹≠H) maybe optionally substituted withX¹¹ or X¹²;

Z is selected from O, N, CH or CR;

W may be present or absent, and if W is present, W is selected from C═O,C═S, C(═N—CN), or S(O₂);

Q may be present or absent, and when Q is present, Q is CH, N, P,(CH₂)_(p), (CHR)_(p), (CRR′)_(p), O, N(R), S, or S(O₂); and when Q isabsent, M may be present or absent; when Q and M are absent, A isdirectly linked to L;

A is O, CH₂, (CHR)_(p), (CHR—CHR′)_(p), (CRR′)_(p), N(R), S, S(O₂) or abond;

E is CH, N, CR, or a double bond towards A, L or G;

G may be present or absent, and when G is present, G is (CH₂)_(p),(CHR)_(p), or (CRR′)_(p); and when G is absent, J is present and E isdirectly connected to the carbon atom in Formula I as G is linked to;

J may be present or absent, and when J is present, J is (CH₂)_(p),(CHR)_(p), or (CRR′)_(p), S(O₂), NH, N(R) or O; and when J is absent, Gis present and E is directly linked to N shown in Formula I as linked toJ;

L may be present or absent, and when L is present, L is CH, C(R), O, Sor N(R); and when L is absent, then M may be present or absent; and if Mis present with L being absent, then M is directly and independentlylinked to E, and J is directly and independently linked to E;

M may be present or absent, and when M is present, M is O, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p)(CHR—CHR′)_(p), or (CRR′) p;

p is a number from 0 to 6; and

R, R′, R², R³ and R⁴ can be the same or different, each beingindependently selected from the group consisting of H; C₁-C₁₀ alkyl;C₂-C₁₀ alkenyl; C₃-C₈ cycloalkyl; C₃-C₈ heterocycloalkyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro, halogen,(cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkylis made of three to eight carbon atoms, and zero to six oxygen,nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to sixcarbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionallysubstituted, with said term “substituted” referring to substitution withone or more moieties which can be the same or different, each beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy,thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester,carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, andhydroxamate;

further wherein said unit N—C-G-E-L-J-N represents a five-memberedcyclic ring structure or six-membered cyclic ring structure with theproviso that when said unit N—C-G-E-L-J-N represents a five-memberedcyclic ring structure, or when the bicyclic ring structure in Formula Icomprising N, C, G, E, L, J, N, A, Q, and M represents a five-memberedcyclic ring structure, then said five-membered cyclic ring structurelacks a carbonyl group as part of said five-membered cyclic ring.

In another embodiment, the inhibitor is a compound of Formula V

or a pharmaceutically acceptable salt, solvate or ester of said compoundwherein:(1) R¹ is —C(O)R⁵ or —B(OR)₂;(2) R⁵ is H, —OH, —OR⁸, —NR⁹R¹⁰, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —CF₃, —C₂F₅,C₃F₇, —CF₂R⁶, —R⁶, —C(O)R⁷ or NR⁷SO₂R⁸;(3) R⁷ is H, —OH, —OR⁸, or —CHR⁹R¹⁰;(4) R⁶, R⁸, R⁹ and R¹⁰ are independently selected from the groupconsisting of H: alkyl, alkenyl, aryl, heteroalkyl, heteroaryl,cycloalkyl, arylalkyl, heteroarylalkyl, R¹⁴,—CH(R^(1′))CH(R^(1′))C(O)OR¹¹, [CH(R^(1′))]_(p)C(O)OR¹¹,—[CH(R^(1′))]_(p)C(O)NR¹²R¹³, —[CH(R^(1′))]_(p)S(O₂)R¹¹,—[CH(R^(1′))]_(p)C(O)R¹¹, —[CH(R^(1′))]_(p)S(O₂)NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))(R′), CH(R^(1′))CH(R^(1′))C(O)NR¹²R¹³,—CH(R^(1′))CH(R^(1′))S(O₂)R¹¹, —CH(R^(1′))CH(R^(1′))S(O₂)NR¹²R¹³,—CH(R^(1′))CH(R^(1′))C(O)R¹¹, —[CH(R^(1′))]_(p)CH(OH)R¹¹,—CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)OR¹¹, C(O)N(H)CH(R^(2′))C(O)OR¹¹,—C(O)N(H)CH(R^(2′))C(O)R¹¹, CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)NR¹²R¹³,—CH(R^(1′))C(O)N(H)CH(R^(2′))R′,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)OR¹¹,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)CH(R^(3′))NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)OR¹¹,H(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)N(H)CH(R^(5′))C(O)OR¹¹,andCH(R^(1′))C(O)N(H)CH(R²′)C(O)N(H)CH(R³′)C(O)N(H)CH(R⁴′)C(O)N(H)CH(R⁵′)C(O)NR¹²R¹³;wherein R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), R¹¹, R¹² and R¹³ can bethe same or different, each being independently selected from the groupconsisting of: H, halogen, alkyl, aryl, heteroalkyl, heteroaryl,cycloalkyl, alkoxy, aryloxy, alkenyl, alkynyl, alkyl-aryl,alkyl-heteroaryl, heterocycloalkyl, aryl-alkyl and heteroaralkyl; orR¹² and R¹³ are linked together wherein the combination is cycloalkyl,heterocycloalkyl, ary or heteroaryl;R¹⁴ is present or not and if present is selected from the groupconsisting of: H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl,alkyl-aryl, allyl, alkyl-heteroaryl, alkoxy, aryl-alkyl, alkenyl,alkynyl and heteroaralkyl;(5) R and R′ are present or not and if present can be the same ordifferent, each being independently selected from the group consistingof: H, OH, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₃-C₈ cycloalkyl, C₃-C₈heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino,arylamino, amino, amido, arylthioamino, arylcarbonylamino,arylaminocarboxy, alkylaminocarboxy, heteroalkyl, alkenyl, alkynyl,(aryl)alkyl, heteroarylalkyl, ester, carboxylic acid, carbamate, urea,ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl, aryl,heteroaryl, (alkyl)aryl, alkylheteroaryl, alkyl-heteroaryl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms;(6) L′ is H, OH, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, orheterocyclyl;(7) M′ is H, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl,arylalkyl, heterocyclyl or an amino acid side chain;or L′ and M′ are linked together to form a ring structure wherein theportion of structural Formula 1 represented by

is represented by structural Formula 2:

wherein in Formula 2:E is present or absent and if present is C, CH, N or C(R);J is present or absent, and when J is present, J is (CH₂)_(p),(CHR—CHR′)_(p), (CHR)_(p), (CRR′)_(p), S(O₂), N(H), N(R) or O; when J isabsent and G is present, L is directly linked to the nitrogen atommarked position 2;p is a number from 0 to 6;L is present or absent, and when L is present, L is C(H) or C(R); when Lis absent, M is present or absent; if M is present with L being absent,then M is directly and independently linked to E, and J is directly andindependently linked to E;G is present or absent, and when G is present, G is (CH₂)_(p),(CHR)_(p), (CHR—CHR′)_(p) or (CRR′)_(p); when G is absent, J is presentand E is directly connected to the carbon atom marked position 1;Q is present or absent, and when Q is present, Q is NR, PR, (CR═CR),(CH₂)_(p), (CHR)_(p), (CRR′)_(p), (CHR—CHR′)_(p), O, NR, S, SO, or SO₂;when Q is absent, M is (i) either directly linked to A or (ii) anindependent substituent on L, said independent substituent bing selectedfrom —OR, —CH(R)(R′), S(O)₀₋₂R or —NRR′ or (iii) absent; when both Q andM are absent, A is either directly linked to L, or A is an independentsubstituent on E, said independent substituent bing selected from —OR,—CH(R)(R′), S(O)₀₋₂R or —NRR′ or A is absent;A is present or absent and if present A is O, O(R), (CH₂)_(p),(CHR)_(p), (CHR—CHR′)_(p), (CRR′)_(p), N(R), NRR′, S, S(O₂), —OR,CH(R)(R′) or NRR′; or A is linked to M to form an alicyclic, aliphaticor heteroalicyclic bridge;M is present or absent, and when M is present, M is halogen, O, OR,N(R), S, S(O₂), (CH₂)_(p), (CHR)_(p) (CHR—CHR′)_(p), or (CRR′)_(p); or Mis linked to A to form an alicyclic, aliphatic or heteroalicyclicbridge;(8) Z′ is represented by the structural Formula 3:

wherein in Formula 3, Y is selected from the group consisting of: H,aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, heteroalkyl-heteroaryl,heteroalkyl-heterocycloalkyl, cycloalkyloxy, alkylamino, arylamino,alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino andheterocycloalkylamino, and Y is unsubstituted or optionally substitutedwith one or two substituents which are the same or different and areindependently selected from X¹¹ or X¹²;X¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl, and X¹¹ is unsubstituted oroptionally substituted with one or more of X¹² moieties which are thesame or different and are independently selected;X¹² is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, thio,alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy,carboxamido, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl,heteroarylcarbonyl, sulfonylurea, cycloalkylsulfonamido,heteroaryl-cycloalkylsulfonamido, heteroaryl-sulfonamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,halogen, cyano, or nitro, and said alkyl, alkoxy, and aryl areunsubstituted or optionally independently substituted with one or moremoieties which are the same or different and are independently selectedfrom alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl;Z is O, N, C(H) or C(R);R³¹ is H, hydroxyl, aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy,aryloxy, heteroaryloxy, heterocycloalkyloxy, heteroalkyl-heteroaryl,cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino or heterocycloalkylamino, and R³¹ isunsubstituted or optionally substituted with one or two substituentswhich are the same or different and are independently selected from X¹³or X¹⁴;X¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl, and X¹³ is unsubstituted oroptionally substituted with one or more of X¹⁴ moieties which are thesame or different and are independently selected;X¹⁴ is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, thio,alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy,carboxamido, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl,heteroarylcarbonyl, cycloalkylsulfonamido,heteroaryl-cycloalkylsulfonamido, heteroarylsulfonamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,halogen, cyano, or nitro, and said alkyl, alkoxy, and aryl areunsubstiuted or optionally independently substituted with one or moremoieties which are the same or different and are independently selectedfrom alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl;W may be present or absent, and if W is present, W is C(═O), C(═S),C(═N—CN), or S(O₂);

(9) X is represented by structural Formula 4:

wherein in Formula 4, a is 2, 3, 4, 5, 6, 7, 8 or 9;b, c, d, e and fare 0, 1, 2, 3, 4 or 5;A is C, N, S or O;R²⁹ and R^(29′) are independently present or absent and if present canbe the same or different, each being independently one or twosubstituents independently selected from the group consisting of: H,halo, alkyl, aryl, cycloalkyl, cycloalkylamino, cycloalkylaminocarbonyl,cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, carboxyl, C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl,aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl,hydroxyalkyl, aryloxy, aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl,heterocyclyl, heterocyclenyl, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—,wherein Y₁ and Y₂ can be the same or different and are independentlyselected from the group consisting of hydrogen, alkyl, aryl, andaralkyl; orR²⁹ and R^(29′) are linked together such that the combination is analiphatic or heteroaliphatic chain of 0 to 6 carbons;R³⁰ is present or absent and if present is one or two substituentsindependently selected from the group consisting of: H, alkyl, aryl,heteroaryl and cylcoalkyl;

(10) D is represented by structural Formula 5:

wherein in Formula 5, R³², R³³ and R³⁴ are present or absent and ifpresent are independently one or two substituents independently selectedfrom the group consisting of: H, halo, alkyl, aryl, cycloalkyl,cycloalkylamino, spiroalkyl, cycloalkylaminocarbonyl, cyano, hydroxy,alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂,carboxyl, —C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl, aralkenyl,heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxyalkyl, aryloxy,aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl,arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkenyl, heterocyclyl, heterocyclenyl,Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ can be thesame or different and are independently selected from the groupconsisting of hydrogen, alkyl, aryl, and aralkyl; orR³² and R³⁴ are linked together such that the combination forms aportion of a cycloalkyl group;g is 1, 2, 3, 4, 5, 6, 7, 8 or 9;h, i, j, k, l and m are 0, 1, 2, 3, 4 or 5; andA is C, N, S or O,

(11) provided that when structural Formula 2:

W′ is CH or N, both the following conditional exclusions (i) and (ii)apply:conditional exclusion (i): Z′ is not —NH—R³⁶, wherein R³⁶ is H,C_(6 or 10) aryl, heteroaryl, —C(O)—R³⁷, —C(O)OR³⁷ or —C(O)NHR³⁷,wherein R³⁷ is C₁₋₆ alkyl or C₃₋₆ cycloalkyl; andconditional exclusion (ii): R¹ is not —C(O)OH, a pharmaceuticallyacceptable salt of —C(O)OH, an ester of —C(O)OH or —C(O)NHR³⁸ whereinR³⁸ is selected from the group consisting of C₁₋₈ alkyl, C₃₋₆cycloalkyl, C_(6 to 10) aryl or C₇₋₁₆ aralkyl.

In another embodiment, the “at least one compound” is a compound offormula VI:

or a pharmaceutically acceptable salt, solvate or ester of saidcompound, wherein:

Cap is H, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino,carboxyalkylamino, arlylalkyloxy or heterocyclylamino, wherein each ofsaid alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino,carboxyalkylamino, arlylalkyloxy or heterocyclylamino can beunsubstituted or optionally independently substituted with one or twosubstituents which can be the same or different and are independentlyselected from X¹ and X²;

P′ is —NHR;

X¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl,arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, orheteroarylalkyl, and X¹ can be unsubstituted or optionally independentlysubstituted with one or more of X² moieties which can be the same ordifferent and are independently selected;

X² is hydroxy, alkyl, aryl, alkoxy, aryloxy, thio, alkylthio, arylthio,amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,halogen, cyano, keto, ester or nitro, wherein each of said alkyl,alkoxy, and aryl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same or differentand are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino,alkylheteroaryl and heteroarylalkyl;

W may be present or absent, and when W is present W is C(═O), C(═S),C(═NH), C(═N—OH), C(═N—CN), S(O) or S(O₂);

Q maybe present or absent, and when Q is present, Q is N(R), P(R),CR═CR′, (CH₂)_(p), (CHR)_(p), (CRR′)_(p), (CHR—CHR′)_(p), O, S, S(O) orS(O₂); when Q is absent, M is (i) either directly linked to A or (ii) Mis an independent substituent on L and A is an independent substituenton E, with said independent substituent being selected from —OR, —CH(R),S(O)₀₋₂R or —NRR′; when both Q and M are absent, A is either directlylinked to L, or A is an independent substituent on E, selected from —OR,CH(R)(R′), —S(O)₀₋₂R or —NRR′;

A is present or absent and if present A is —O—, —O(R)CH₂—, —(CHR)_(p)—,—(CHR—CHR′)_(p)—, (CRR′)_(p), N(R), NRR′, S, or S(O₂), and when Q isabsent, A is —OR, —CH(R)(R′) or —NRR′; and when A is absent, either Qand E are connected by a bond or Q is an independent substituent on M;

E is present or absent and if present E is CH, N, C(R);

G may be present or absent, and when G is present, G is (CH₂)_(p),(CHR)_(p), or (CRR′)_(p); when G is absent, J is present and E isdirectly connected to the carbon atom marked position 1;

J may be present or absent, and when J is present, J is (CH₂)_(p),(CHR—CHR′)_(p), (CHR)_(p), (CRR′)_(p), S(O₂), N(H), N(R) or O; when J isabsent and G is present, L is directly linked to the nitrogen atommarked position 2;

L may be present or absent, and when L is present, L is CH, N, or CR;when L is absent, M is present or absent; if M is present with L beingabsent, then M is directly and independently linked to E, and J isdirectly and independently linked to E;

M may be present or absent, and when M is present, M is O, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p), (CHR—CHR′)_(p), or (CRR′)_(p);

p is a number from 0 to 6;

R, R′ and R³ can be the same or different, each being independentlyselected from the group consisting of: H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, alkoxy, aryloxy, alkylthio,arylthio, amino, amido, arylthioamino, arylcarbonylamino,arylaminocarboxy, alkylaminocarboxy, heteroalkyl, heteroalkenyl,alkenyl, alkynyl, aryl-alkyl, heteroarylalkyl, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro, halogen,(cycloalkyl)alkyl, aryl, heteroaryl, alkyl-aryl, alkylheteroaryl,alkyl-heteroaryl and (heterocyclyl)alkyl;

R and R′ in (CRR′) can be linked together such that the combinationforms a cycloalkyl or heterocyclyl moiety; and

R¹ is carbonyl.

In another embodiment, the inhibitor is a compound of Formula VII

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein,

M is O, N(H), or CH₂;

n is 0-4;

R¹ is —OR⁶, —NR⁶R⁷ or

where R⁶ and R⁷ can be the same or different, each being independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino,arylamino and alkylamino;R⁴ and R⁵ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, aryl and cycloalkyl; oralternatively R⁴ and R⁵ together form part of a cyclic 5- to 7-memberedring such that the moiety

is represented by

where k is 0 to 2;X is selected from the group consisting of:

where p is 1 to 2, q is 1-3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; andR³ is selected from the group consisting of: aryl, heterocyclyl,heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy.

In another embodiment, the “at least one compound” is a compound offormula formula VIII:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein,

M is O, N(H), or CH₂;

R¹ is —C(O)NHR⁶, where R⁶ is hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino,arylamino or alkylamino;

P₁ is selected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl haloalkyl;

P₃ is selected from the group consisting of alkyl, cycloalkyl, aryl andcycloalkyl fused with aryl;

R⁴ and R⁵ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, aryl and cycloalkyl; oralternatively R⁴ and R⁵ together form part of a cyclic 5- to 7-memberedring such that the moiety

is represented by

where k is 0 to 2;

X is selected from the group consisting of:

where p is 1 to 2, q is 1 to 3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and

R³ is selected from the group consisting of: aryl, heterocyclyl,heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy.

In another embodiment, the “at least one compound” is a compound offormula IX:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein,

M is O, N(H), or CH₂;

n is 0-4;

R¹ is —OR⁶, —NR⁶R⁷ or

where R⁶ and R⁷ can be the same or different, each being independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino,arylamino and alkylamino;R⁴ and R⁵ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, aryl and cycloalkyl; oralternatively R⁴ and R⁵ together form part of a cyclic 5- to 7-memberedring such that the moiety

is represented by

where k is 0 to 2;X is selected from the group consisting of:

where p is 1 to 2, q is 1 to 3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; andR³ is selected from the group consisting of: aryl, heterocyclyl,heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy. In anotherembodiment, the “at least one compound” is a compound of formula X:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, orheteroarylalkyl;

A and M can be the same or different, each being independently selectedfrom R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected toeach other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl;

E is C(H) or C(R);

L is C(H), C(R), CH₂C(R), or C(R)CH₂;

R, R′, R², and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl-, alkenyl-, alkynyl-,cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to eachother such that NRR′ forms a four to eight-membered heterocyclyl;

and Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, R¹⁵ and R¹⁶ are connected to eachother to form a four to eight-membered cycloalkyl, heteroaryl orheterocyclyl structure, and likewise, independently R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of: hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.

In one embodiment, the “at least one compound” is a compound of FormulaXI:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, orheteroarylalkyl;

A and M can be the same or different, each being independently selectedfrom R, NR⁹R¹⁰, SR, SO₂R, and halo; or A and M are connected to eachother (in other words, A-E-L-M taken together) such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl;

E is C(H) or C(R);

L is C(H), C(R), CH₂C(R), or C(R)CH₂;

R, R′, R², and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl-, alkenyl-, alkynyl-,cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to eachother such that NR⁹R¹⁰ forms a four to eight-membered heterocyclyl;

Y is selected from the following moieties:

wherein Y³⁰ and Y³¹ are selected from

X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O) and SO₂;

G is NH or O; and

R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, T₃ and T₄ can be the same or different,each being independently selected from the group consisting of H, alkyl,heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, oralternately, R¹⁷ and R¹⁸ are connected to each other to form a three toeight-membered cycloalkyl or heterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of: hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.

In another embodiment, the “at least one compound” is a compound offormula XII:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, orheteroarylalkyl;

A and M can be the same or different, each being independently selectedfrom R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected toeach other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl;

E is C(H) or C(R);

L is C(H), C(R), CH₂C(R), or C(R)CH₂;

R, R′, R², and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl-, alkenyl-, alkynyl-,cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to eachother such that NRR′ forms a four to eight-membered heterocyclyl;

and Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, (i) either R¹⁵ and R¹⁶ areconnected to each other to form a four to eight-membered cyclicstructure, or R¹⁵ and R¹⁹ are connected to each other to form a four toeight-membered cyclic structure, and (ii) likewise, independently, R¹⁷and R¹⁸ are connected to each other to form a three to eight-memberedcycloalkyl or heterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of: hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkylsulfonamido,arylsulfonamido, alkyl, aryl, heteroaryl, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.

In another embodiment, the “at least one compound” is a compound ofFormula XIII:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, orheteroarylalkyl;

A and M can be the same or different, each being independently selectedfrom R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected toeach other (in other words, A-E-L-M taken together) such that themoiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl;

E is C(H) or C(R);

L is C(H), C(R), CH₂C(R), or C(R)CH₂;

R, R′, R², and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl-, alkenyl-, alkynyl-,cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to eachother such that NRR′ forms a four to eight-membered heterocyclyl;and Y is selected from the following moieties:

wherein G is NH or O, and R¹⁵, R¹⁶, R¹⁷R¹⁸, R¹⁹ and R²⁰ can be the sameor different, each being independently selected from the groupconsisting of H, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ heteroalkenyl, C₂-C₁₀ alkynyl, C₂-C₁₀ heteroalkynyl, C₃-C₈cycloalkyl, C₃-C₈ heterocyclyl, aryl, heteroaryl, or alternately: (i)either R¹⁵ and R¹⁶ can be connected to each other to form a four toeight-membered cycloalkyl or heterocyclyl, or R¹⁵ and R¹⁹ are connectedto each other to form a five to eight-membered cycloalkyl orheterocyclyl, or R¹⁵ and R²⁰ are connected to each other to form a fiveto eight-membered cycloalkyl or heterocyclyl, and (ii) likewise,independently, R¹⁷ and R¹⁸ are connected to each other to form a threeto eight-membered cycloalkyl or heterocyclyl,

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of: hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkylsulfonamido,arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo,cyano, and nitro.

In another embodiment, the “at least one compound” is a compound ofFormula XIV:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, orheteroarylalkyl;

A and M can be the same or different, each being independently selectedfrom R, OR, NHR, NRR′, SR, SO₂R, and halo;or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl;

E is C(H) or C═;

L is C(H), C═, CH₂C═, or C═CH₂;

R, R′, R², and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, or alternately R and R′ inNRR′ are connected to each other such that NRR′ forms a four toeight-membered heterocyclyl;

and Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, oralternately, (i) R¹⁵ and R¹⁶ are connected to each other to form a fourto eight-membered cyclic structure, and (ii) likewise, independently R¹⁷and R¹⁸ are connected to each other to form a three to eight-memberedcycloalkyl or heterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of: hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkylsulfonamido,arylsulfonamido, alkyl, aryl, heteroaryl, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.

In another embodiment, the “at least one compound” is a compound ofFormula XV:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

R¹ is NHR⁹, wherein R⁹ is H, alkyl-, aryl-, heteroalkyl-, heteroaryl-,cycloalkyl-, cycloalkyl-, arylalkyl-, or heteroarylalkyl;

E and J can be the same or different, each being independently selectedfrom the group consisting of R, OR, NHR, NRR⁷, SR, halo, and S(O₂)R, orE and J can be directly connected to each other to form either a threeto eight-membered cycloalkyl, or a three to eight-membered heterocyclylmoiety;

Z is N(H), N®, or O, with the proviso that when Z is O, G is present orabsent and if G is present with Z being O, then G is C(═O);

G maybe present or absent, and if G is present, G is C(═O) or S(O₂), andwhen G is absent, Z is directly connected to Y;

Y is selected from the group consisting of:

R, R⁷, R², R³, R⁴ and R⁵ can be the same or different, each beingindependently selected from the group consisting of H, alkyl-, alkenyl-,alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-, wherein each of said heteroalkyl, heteroaryl andheterocyclyl independently has one to six oxygen, nitrogen, sulfur, orphosphorus atoms;

wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl and heterocyclyl moieties can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl,cycloalkyl, heterocyclyl, halo, hydroxy, thio, alkoxy, aryloxy,alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate,urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone,sulfonyl urea, hydrazide, and hydroxamate.

In another embodiment, the “at least one compound” is a compound ofFormula XVI:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, orheteroarylalkyl;

R² and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl;

Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³,R²⁴ and R²⁵ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R¹⁷ andR¹⁸ are independently connected to each other to form a three toeight-membered cycloalkyl or heterocyclyl; (ii) likewise independentlyR¹⁵ and R¹⁹ are connected to each other to form a four to eight-memberedheterocyclyl; (iii) likewise independently R¹⁵ and R¹⁶ are connected toeach other to form a four to eight-membered heterocyclyl; (iv) likewiseindependently R¹⁵ and R²⁰ are connected to each other to form a four toeight-membered heterocyclyl; (v) likewise independently R²² and R²³ areconnected to each other to form a three to eight-membered cycloalkyl ora four to eight-membered heterocyclyl; and (vi) likewise independentlyR²⁴ and R²⁵ are connected to each other to form a three toeight-membered cycloalkyl or a four to eight-membered heterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.

In another embodiment, the “at least one compound” is a compound ofFormula XVII:

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:

R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, orheteroarylalkyl;

A and M can be the same or different, each being independently selectedfrom R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected toeach other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl;

E is C(H) or C═;

L is C(H), C═, CH₂C═, or C═CH₂;

R, R′, R², and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl-, alkenyl-, alkynyl-,cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to eachother such that NRR′ forms a four to eight-membered heterocyclyl;

Y is selected from the following moieties:

wherein Y³⁰ is selected from

-   -   where u is a number 0-1;

X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O) and SO₂;

G is NH or O; and

R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, and T₃ can be the same or different,each being independently selected from the group consisting of H, alkyl,heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, oralternately, R¹⁷ and R¹⁸ are connected to each other to form a three toeight-membered cycloalkyl or heterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of: hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.

In another embodiment, the inhibitor is a compound of Formula XVIII:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein:R⁸ is selected from the group consisting of alkyl-, aryl-, heteroalkyl-,heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, heteroarylalkyl-,and heterocyclylalkyl;R⁹ is selected from the group consisting of H, alkyl, alkenyl, alkynyl,aryl and cycloalkyl;A and M can be the same or different, each being independently selectedfrom R, OR, N(H)R, N(RR′), SR, S(O₂)R, and halo; or A and M areconnected to each other (in other words, A-E-L-M taken together) suchthat the moiety:

shown above in Formula I forms either a three, four, five, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl;

E is C(H) or C(R);

L is C(H), C(R), CH₂C(R), or C(R)CH₂;

R and R′ can be the same or different, each being independently selectedfrom the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in N(RR′) are connected to each other such that N(RR′) forms afour to eight-membered heterocyclyl;

R² and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, spiro-linkedcycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl;

Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately (i) R¹⁷ and R¹⁸ are independentlyconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; (ii) likewise independently R¹⁵ and R¹⁹ are connected toeach other to form a four to eight-membered heterocyclyl; (iii) likewiseindependently R¹⁵ and R¹⁶ are connected to each other to form a four toeight-membered heterocyclyl; and (iv) likewise independently R¹⁵ and R²⁰are connected to each other to form a four to eight-memberedheterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, spiro-linkedcycloalkyl, and heterocyclyl can be unsubstituted or optionallyindependently substituted with one or more moieties selected from thegroup consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio,amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,sulfonamido, alkyl, alkenyl, aryl, heteroaryl, alkylsulfonamido,arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo,cyano, and nitro.

In another embodiment, the “at least one compound” is a compound ofFormula XIX:

wherein:

Z is selected from the group consisting of a heterocyclyl moiety,N(H)(alkyl), —N(alkyl)₂, —N(H)(cycloalkyl), —N(cycloalkyl)₂, —N(H)(aryl,—N(aryl)₂, —N(H)(heterocyclyl), —N(heterocyclyl)₂, —N(H)(heteroaryl),and —N(heteroaryl)₂;

R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, orheteroarylalkyl;

R² and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl;

Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ can bethe same or different, each being independently selected from the groupconsisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately (i) R¹⁷ and R¹⁸ are indenpendentlyconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; (ii) likewise independently R¹⁵ and R¹⁹ are connected toeach other to form a four to eight-membered heterocyclyl; (iii) likewiseindependently R¹⁵ and R¹⁶ are connected to each other to form a four toeight-membered heterocyclyl; and (iv) likewise independently R¹⁵ and R²⁰are connected to each other to form a four to eight-memberedheterocyclyl;

wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro.In another embodiment, the inhibitor is a compound of Formula XX

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: a is 0 or 1; b is 0 or 1; Y is H or C₁₋₆ alkyl;B is H, an acyl derivative of formula R₇—C(O)— or a sulfonyl of formulaR₇—SO2 whereinR7 is (i) C_(l-10) alkyl optionally substituted with carboxyl, C₁₋₆alkanoyloxy or C₁₋₆ alkoxy;

-   -   (ii) C₃₋₇ cycloalkyl optionally substituted with carboxyl,        (C_(l-6) alkoxy)carbonyl or phenylmethoxycarbonyl;    -   (iii) C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substituted        with C₁₋₆ alkyl, hydroxy, or amino optionally substituted with        C₁₋₆ alkyl; or    -   (iv) Het optionally substituted with C₁₋₆ alkyl, hydroxy, amino        optionally substituted with C₁₋₆ alkyl, or amido optionally        substituted with C₁₋₆ alkyl;        R₆, when present, is C₁₋₆ alkyl substituted with carboxyl;        R₅, when present, is C₁₋₆ alkyl optionally substituted with        carboxyl;        R₄ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl or C₄₋₁₀ (alkylcycloalkyl);        R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl or C₄₋₁₀ (alkylcycloalkyl);        R₂ is CH₂—R₂₀, NH—R₂₀, O—R₂₀ or S—R₂₀, wherein R₂₀ is a        saturated or unsaturated C₃₋₇ cycloalkyl or C₄₋₁₀ (alkyl        cycloalkyl) being optionally mono-, di- or tri-substituted with        R₂₁, or R₂₀ is a C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally        mono-, di- or tri-substituted with R₂₁,        or R₂₀ is Het or (lower alkyl)-Het optionally mono-, di- or        tri-substituted with R₂₁, wherein each R₂₁ is independently C₁₋₆        alkyl; C₁₋₆alkoxy; amino optionally mono- or di-substituted with        C₁₋₆ alkyl; sulfonyl; NO₂; OH; SH; halo; haloalkyl; amido        optionally mono-substituted with C₁₋₆ alkyl, C₆ or C₁₀ aryl,        C₇₋₁₆ aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower        alkyl); C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl or Het, said aryl, aralkyl        or Het being optionally substituted with R₂₂;        wherein R₂₂ is C₁₋₆alkyl; C₁₋₆ alkoxy; amino optionally mono- or        di-substituted with C₁₋₆ alkyl; sulfonyl; N0₂; OH; SH; halo;        haloalkyl; carboxyl; amide or (lower alkyl)amide;        R₁ is C₁₋₆ alkyl or C₂₋₆ alkenyl optionally substituted with        halogen; and        W is hydroxy or a N-substituted amino.

In the above-shown structure of the compound of Formula XX, the termsP6, P5, P4, P3, P2 and P1 denote the respective amino acid moieties asis conventionally known to those skilled in the art.

In another embodiment, the inhibitor is a compound of Formula XXI

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:B is H, a C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl; Het or (lower alkyl)-Het, allof which optionally substituted with C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano;cyanoalkyl; amino optionally substituted with C₁₋₆ alkyl; amido; or(lower alkyl)amide;or B is an acyl derivative of formula R₄—C(O)—; a carboxyl of formulaR₄-0-C(O)—; an amide of formula R₄—N(R₅)—C(O)—; a thioamide of formulaR₄—N(R₅)—C(S)—; or a sulfonyl of formula R₄—SO2 wherein

R₄ is (i) C₁₋₁₀ alkyl optionally substituted with carboxyl, C₁₋₆alkanoyl, hydroxy, C₁₋₆ alkoxy, amino optionally mono- or di-substitutedwith C₁₋₆ alkyl, amido, or (lower alkyl)amide;

(ii) C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy, or C₄₋₁₀ alkylcycloalkyl, alloptionally substituted with hydroxy, carboxyl, (C₁₋₆ alkoxy)carbonyl,amino optionally mono- or di-substituted with C₁₋₆ alkyl, amido, or(lower alkyl) amide;

(iii) amino optionally mono- or di-substituted with C₁₋₆ alkyl; amido;or (lower alkyl)amide;

(iv) C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl, all optionally substituted withC₁₋₆ alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionallymono- or di-substituted with C₁₋₆ alkyl; or

(v) Het or (lower alkyl)-Het, both optionally substituted with C₁₋₆alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono- ordi-substituted with C₁₋₆ alkyl;

R₅ is H or C₁₋₆ alkyl;

with the proviso that when R₄ is an amide or a thioamide, R₄ is not (ii)a cycloalkoxy;

Y is H or C₁₋₆ alkyl;

R₃ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, or C₄₋₁₀ alkylcycloalkyl, alloptionally substituted with hydroxy, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, amido,(lower alkyl)amido, C₆ or C₁₀ aryl, or C₇₋₁₆ aralkyl;

R₂ is CH₂—R₂₀, NH—R₂₀, O—R₂₀ or S—R₂₀, wherein R₂₀ is a saturated orunsaturated C₃₋₇ cycloalkyl or C₄₋₁₀ (alkylcycloalkyl), all of whichbeing optionally mono-, di- or tri-substituted with R₂₁, or R₂₀ is a C₆or C₁₀ aryl or C₇₋₁₄ aralkyl, all optionally mono-, di- ortri-substituted with R₂₁,

or R₂₀ is Het or (lower alkyl)-Het, both optionally mono-, di- ortri-substituted with R₂₁,

wherein each R₂₁ is independently C₁₋₆ alkyl; C₁₋₆ alkoxy; lowerthioalkyl; sulfonyl; N0₂; OH; SH; halo; haloalkyl; amino optionallymono- or di-substituted with C₁₋₆ alkyl, C₆ or C₁₀ aryl, C₇₋₁₄ aralkyl,Het or (lower alkyl)-Het; amido optionally mono-substituted with C₁₋₆alkyl, C₆ or C₁₀ aryl, C₇₋₁₄ aralkyl, Het or (lower alkyl)-Het;carboxyl; carboxy(lower alkyl); C₆ or C₁₀ aryl, C₇₋₁₄ aralkyl or Het,said aryl, aralkyl or Het being optionally substituted with R₂₂;

wherein R₂₂ is C₁₋₆ alkyl; C₃₋₇ cycloalkyl; C₁₋₆ alkoxy; aminooptionally mono- or di-substituted with C₁₋₆ alkyl; sulfonyl; (loweralkyl)sulfonyl; N0₂; OH; SH; halo; haloalkyl; carboxyl; amide; (loweralkyl)amide; or Het optionally substituted with C₁₋₆ alkyl;

R1 is H; C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, alloptionally substituted with halogen.

In another embodiment, the inhibitor is a compound of Formula XXII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinW is CH or N,R²¹ is H, halo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₃₋₆ cycloalkoxy, hydroxy, or N(R²³)₂, wherein each R²³ isindependently H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl;R²² is H, halo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆thioalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, C₂₋₇ alkoxyalkyl, C₃₋₆cycloalkyl, C_(6 or 10) aryl or Het, wherein Het is a five-, six-, orseven-membered saturated or unsaturated heterocycle containing from oneto four heteroatoms selected from nitrogen, oxygen and sulfur;said cycloalkyl, aryl or Het being substituted with R²⁴, wherein R²⁴ isH, halo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy,NO₂, N(R²⁵)₂, NH—C(O)—R²⁵ or NH—C(O)—NH—R²⁵, wherein each R²⁵ isindependently: H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; or R²⁴ is NH—C(O)—OR²⁶wherein R²⁶ is C₁₋₆ alkyl or C₃₋₆ cycloalkyl;R³ is hydroxy, NH₂, or a group of formula —NH—R³¹, wherein R³¹ isC_(6 or 10) aryl, heteroaryl, —C(O)—R³², —C(O)—NHR³² or —C(O)—OR³²,wherein R³² is C₁₋₆ alkyl or C₃₋₆ cycloalkyl;D is a 5 to 10-atom saturated or unsaturated alkylene chain optionallycontaining one to three heteroatoms independently selected from: O, S,or N—R⁴¹, wherein R⁴¹ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or —C(O)—R⁴²,wherein R⁴² is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or C_(6 or 10) aryl; R⁴ is Hor from one to three substituents at any carbon atom of said chain D,said substituent independently selected from the group consisting of:C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, hydroxy, halo, amino, oxo, thioand C₁₋₆ thioalkyl, and A is an amide of formula —C(O)—NH—R⁵, wherein R⁵is selected from the group consisting of: C₁₋₈ alkyl, C₃₋₆ cycloalkyl,C_(6 or 10) aryl and C₇₋₁₆ aralkyl;or A is a carboxylic acid.

In another embodiment, the “at least one compound” is a compound offormula XXIII:

a pharmaceutically acceptable salt, solvate or ester thereof; wherein:R⁰ is a bond or difluoromethylene;R¹ is hydrogen;R² and R⁹ are each independently optionally substituted aliphatic group,optionally substituted cyclic group or optionally substituted aromaticgroup;R3, R5 and R7 are each independently:

optionally substituted (1,1- or 1,2-)cycloalkylene; or

optionally substituted (1,1- or 1,2-)heterocyclylene; or

methylene or ethylene), substituted with one substituent selected fromthe group consisting of an optionally substituted aliphatic group, anoptionally substituted cyclic group or an optionally substitutedaromatic group, and wherein the methylene or ethylene is furtheroptionally substituted with an aliphatic group substituent; or; R4, R6,R8 and R¹⁰ are each independently hydrogen or optionally substitutedaliphatic group;

is substituted monocyclic azaheterocyclyl or optionally substitutedmulticyclic azaheterocyclyl, or optionally substituted multicyclicazaheterocyclenyl wherein the unsaturatation is in the ring distal tothe ring bearing the R⁹-L-(N(R⁸)—R⁷—C(O)—)_(n)N(R⁶)—R⁵—C(O)—N moiety andto which the —C(O)—N(R⁴)—R³—C(O)C(O)NR²R¹ moiety is attached; L is—C(O)—, —OC(O)—, —NR¹⁰C(O)—, —S(0)₂—, or —NR¹⁰S(0)₂—; and n is 0 or 1,providedwhen

is substituted

then L is —OC(O)— and R⁹ is optionally substituted aliphatic; or atleast one of R³, R⁵ and R⁷ is ethylene, substituted with one substituentselected from the group consisting of an optionally substitutedaliphatic group, an optionally substituted cyclic group or an optionallysubstituted aromatic group and wherein the ethylene is furtheroptionally substituted with an aliphatic group substituent; or R⁴ isoptionally substituted aliphatic.

In another embodiment, the “at least one compound” is a compound offormula (XXIV):

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein:W is:

m is 0 or 1;

R² is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl,heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroaralkyl;wherein any R² carbon atom is optionally substituted with J;

J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl,cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, keto,hydroxy, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino,carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, formyl,acyl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 J¹groups;

J¹ is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl,heterocyclyloxy, keto, hydroxy, amino, alkanoylamino, aroylamino,carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, formyl,sulfonyl, or sulfonamido;

L is alkyl, alkenyl, or alkynyl, wherein any hydrogen is optionallysubstituted with halogen, and wherein any hydrogen or halogen atom boundto any terminal carbon atom is optionally substituted with sulfhydryl orhydroxy;

A¹ is a bond;

R⁴ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and isoptionally substituted with 1-3 J groups;

R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, aryl, aralkyl,aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionallysubstituted with 1-3 J groups;

X is a bond, —C(H)(R7)-, -0-, —S—, or —N(R8)-;

R⁷ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionallysubstititued with 1-3 J groups;

R⁸ is hydrogen alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, aralkanoyl, heterocyclanoyl,heteroaralkanoyl, —C(O)R¹⁴, —S0₂R¹⁴, or carboxamido, and is optionallysubstititued with 1-3 J groups; or R⁸ and Z, together with the atoms towhich they are bound, form a nitrogen containing mono- or bicyclic ringsystem optionally substituted with 1-3 J groups;

R¹⁴ is alkyl, aryl, aralkyl, heterocyclyl, heterocyclyalkyl, heteroaryl,or heteroaralkyl;

Y is a bond, —CH₂—, —C(O)—, —C(O)C(O)—, —S(O)—, —S(0)₂—, or —S(O)(NR⁷)—,wherein R⁷ is as defined above;

Z is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroaralkyl, —OR², or —N(R²)₂, whereinany carbon atom is optionally substituted with J, wherein R² is asdefined above;

A² is a bond or

R⁹ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and isoptionally substituted with 1-3 J groups;

M is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroaralkyl, optionally substituted by 1-3 J groups,wherein any alkyl carbon atom may be replaced by a heteroatom;

V is a bond, —CH₂—, —C(H)(R¹¹)—, -0-, —S—, or —N(R¹¹)—;

R¹¹ is hydrogen or C₁₋₃alkyl;

K is a bond, -0-, —S—, —C(O)—, —S(O)—, —S(0)₂—, or —S(O)(NR¹¹)—, whereinR¹¹ is as defined above;

T is —R¹², -alkyl-R¹², -alkenyl-R¹²-alkynyl-R¹², —OR¹², —N(R¹²)2,—C(O)R¹², —C(═NOalkyl)R¹², or

R¹² is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl,cycloalkylidenyl, or heterocycloalkylidenyl, and is optionallysubstituted with 1-3 J groups, or a first R¹² and a second R¹², togetherwith the nitrogen to which they are bound, form a mono- or bicyclic ringsystem optionally substituted by 1-3 J groups;

R¹⁰ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, orcarboxamidoalkyl, and is optionally substituted with 1-3 hydrogens Jgroups;

R¹⁵ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, orcarboxamidoalkyl, and is optionally substituted with 1-3 J groups; and

R¹⁶ is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.

In another embodiment, the inhibitor is a compound of Formula XXV

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein

E represents CHO or B(OH)₂;

R¹ represents lower alkyl, halo-lower alkyl, cyano-lower alkyl, loweralkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-loweralkyl, heteroaryllower alkyl, lower alkenyl or lower alkynyl;

R² represents lower alkyl, hydroxy-lower alkyl, carboxylower alkyl,aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-loweralkyl; and

R³ represents hydrogen or lower alkyl;

or R² and R³ together represent di- or trimethylene optionallysubstituted by hydroxy;

R⁴ represents lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-loweralkyl, carboxy-lower alkyl, aryllower alkyl, lower alkylthio-loweralkyl, cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-loweralkyl, lower alkenyl, aryl or lower cycloalkyl;

R⁵ represents lower alkyl, hydroxy-lower alkyl, lower alkylthio-loweralkyl, aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-loweralkylthio-lower alkyl or lower cycloalkyl;

R⁶ represents hydrogen or lower alkyl;

R⁷ represent lower alkyl, hydroxydower alkyl, carboxylower alkyl,aryl-iower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl;

R⁸ represents lower alkyl, hydroxy-lower alkyl, carboxylower alkyl oraryl-lower alkyl; and

R⁹ represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl,arylcarbonyl, lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonylor aryl-lower alkoxycarbonyl.

In another embodiment, the “at least one compound” is a compound offormula XXVI:

or a pharmaceutically acceptable salt, solvate or ester thereof; wherein

B is an acyl derivative of formula R₁₁—C(O)— wherein R₁₁ is Cl-10 alkyloptionally substituted with carboxyl; or R₁₁ is C₆ or C₁₀ aryl or C₇₋₁₆aralkyl optionally substituted with a C₁₋₆ alkyl;

a is 0 or 1;

R₆, when present, is carboxy(lower)alkyl;

b is 0 or 1;

R₅, when present, is C₁₋₆ alkyl, or carboxy(lower)alkyl;

Y is H or C₁₋₆ alkyl;

R₄ is C₁₋₁₀ alkyl; C₃₋₁₀ cycloalkyl;

R₃ is C1-10 alkyl; C₃₋₁₀ cycloalkyl;

W is a group of formula:

wherein R₂ is C₁₋₁₀ alkyl or C₃₋₇ cycloalkyl optionally substituted withcarboxyl; C₆ or C₁₀ aryl; or C₇₋₁₆ aralkyl; or

W is a group of formula:

wherein X is CH or N; and

R₂′ is C₃₋₄ alkylene that joins X to form a 5- or 6-membered ring, saidring optionally substituted with OH; SH; NH2; carboxyl; R₁₂; OR₁₂, SR₁₂,NHR₁₂ or NR₁₂R₁₂′ wherein R₁₂ and R₁₂′ are independently:

cyclic C₃₋₁₆ alkyl or acyclic C₁₋₁₆ alkyl or cyclic C₃₋₁₆ alkenyl oracyclic C₂₋₁₆ alkenyl, said alkyl or alkenyl optionally substituted withNH₂, OH, SH, halo, or carboxyl; said alkyl or alkenyl optionallycontaining at least one heteroatom selected independently from the groupconsisting of: 0, S, and N; or

R₁₂ and R₁₂′ are independently C₆ or C₁₀ aryl or C₇₋₁₆ aralkyloptionally substituted with C₁₋₆alkyl, NH₂, OH, SH, halo, carboxyl orcarboxy(lower)alkyl; said aryl or aralkyl optionally containing at leastone heteroatom selected independently from the group consisting of: 0,S, and N;

said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionallyfused with a second 5-, 6-, or 7-membered ring to form a cyclic systemor heterocycle, said second ring being optionally substituted with NH₂.OH, SH, halo, carboxyl or carboxy(lower)alkyl; C₆ or C₁₀ aryl, orheterocycle; said second ring optionally containing at least oneheteroatom selected independently from the group consisting of: 0, S,and N;

Q is a group of the formula:

wherein Z is CH;

X is 0 or S;

R₁ is H, C₁₋₆ alkyl or C₁₋₆ alkenyl both optionally substituted withthio or halo; and

R₁₃ is C0-NH—R₁₄ wherein R₁₄ is hydrogen, cyclic C₃₋₁₀ alkyl or acyclicC₁₋₁₀ alkyl or cyclic C₃₋₁₀ alkenyl or acyclic C₂₋₁₀ alkenyl, said alkylor alkenyl optionally substituted with NH₂, OH, SH, halo or carboxyl;said alkyl or alkenyl optionally containing at least one heteroatomselected independently from the group consisting of: 0, S, and N; or

R₁₄ is C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substituted with C₁₋₆alkyl, NH₂, OH, SH, halo, carboxyl or carboxy(lower)alkyl or substitutedwith a further C₃₋₇ cycloalkyl, C₆ or C₁₀ aryl, or heterocycle; saidaryl or aralkyl optionally containing at least one heteroatom selectedindependently from the group consisting of: 0, S, and N;

said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionallyfused with a second 5-, 6-, or 7-membered ring to form a cyclic systemor heterocycle, said second ring being optionally substituted with NH₂,OH, SH, halo, carboxyl or carboxy(lower)alkyl or substituted with afurther C₃₋₇ cycloalkyl, C₆ or C₁₀ aryl, or heterocycle; said secondring optionally containing at least one heteroatom selectedindependently from the group consisting of: 0, S, and N;

with the proviso that when Z is CH, then R₁₃ is not an α-amino acid oran ester thereof;

Q is a phosphonate group of the formula:

wherein R₁₅ and R₁₆ are independently C₆₋₂₀ aryloxy; and R₁ is asdefined above.

In the above-shown structure of the compound of Formula XXVI, the termsP6, P5, P4, P3, P2 and P1 denote the respective amino acid moieties asis conventionally known to those skilled in the art. Thus, the actualstructure of the compound of Formula XXVI is:

In another embodiment, the compound is selected from the groupconsisting of:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Methods of treating a wide variety of diseases/disorders associated withcathepsin activity and/or for inhibiting cathepsin activity in a subjectcomprising administering to a subject in need of such treatment aneffective amount of at least one of the inventive compounds also areprovided.

One example of such disorders is proliferative diseases, such as cancer,autoimmune diseases, viral diseases, fungal diseases,neurological/neurodegenerative disorders, arthritis, inflammation,anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia andcardiovascular disease. Many of these diseases and disorders are listedin U.S. Pat. No. 6,413,974, the disclosure of which is incorporatedherein.

Another example of a disease that can be treated by the presentcompounds is an inflammatory disease, such as organ transplantrejection, graft v. host disease, arthritis, rheumatoid arthritis,inflammatory bowel disease, atopic dermatitis, psoriasis, asthma,allergies, multiple sclerosis, fixed drug eruptions, cutaneousdelayed-type hypersentitivity responses, tuberculoid leprosy, type Idiabetes, and viral meningitis.

Another example of a disease that can be treated by the presentcompounds is a cardiovascular disease.

Another example of a disease that can be treated by the presentcompounds is a central nervous system disease, such as depression,cognitive function disease, neurodegenerative disease such asParkinson's disease, senile dementia such as Alzheimer's disease, andpsychosis of organic origin.

Other examples of diseases that can be treated by the present compoundsare diseases characterized by bone loss, such as osteoporosis; gingivaldiseases, such as gingivitis and periodontitis; and diseasescharacterized by excessive cartilage or matrix degradation, such asosteoarthritis and rheumatoid arthritis.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified in all instances by the term “about.”

BRIEF DESCRIPTION OF THE DRAWING

The invention is further illustrated by the following drawing in whichFIG. 1 is a graph comparing plasma levels of compound 1a (SCH 503034)measured over time in fasted versus fed (with high fat and low fat diet)subjects.

DETAILED DESCRIPTION

In one embodiment, the present invention provides a method of treating,preventing or ameliorating one or more symptoms of hepatitis C in asubject comprising the step of administering at least one compoundselected from the group consisting of compounds of Formulae I-XXVI incombination with food, as described above.

In another embodiment, the present invention provides a method ofincreasing bioavailability of a compound of Formulae I-XXVI in a subjectcomprising administering the at least one compound of Formulae I-XXVI incombination with food. As used herein, the term “increasingbioavailability” means that more of the compound of Formulae I-XXVI ispresent in the blood when taken with food as compared to no food, asdetermined by measurement of serum levels of the compound of FormulaeI-XXVI after administration. Administration of the compound incombination with food results in higher serum levels of the compound.

As used herein, the term “in combination with food” means that thecompound is administered within about ninety minutes of consumption offood, e.g., no more than about 90 minutes after food is eaten and nomore than about 90 minutes prior to eating food.

In another embodiment, a method of increasing the serum level of acompound of Formulae I-XXVI in a subject is provided. The methodcomprises administering at least one compound in combination with food.

Preferably, the at least one compound(s) are administered in one or morediscrete dosages over twenty-four hours, and the total amount of the atleast one compound of Formulae I-XXVI administered over twenty-fourhours is between 50 mg and 3,000 mg. More preferably, the total amountof the at least one compound of Formulae I-XXVI administered overtwenty-four hours is between 50 mg and 2,400 mg, and even morepreferably, the total amount of the at least one compound of FormulaeI-XXVI administered over twenty-four hours is between 50 mg and 1,200mg.

In some embodiments, the one or more discrete dosages is between one andsix doses over twenty-four hours. In an embodiment, the one or morediscrete dosages are three or four doses in twenty-four hours.

In one embodiment, the one or more discrete dosages are in oral dosageform. The oral dosage form is selected from the group consisting oftablets, capsules, caplets, suspensions, emulsions, troches, lozenges,effervescent tablets, lollipops and reconstitutable powders.

In one embodiment, the at least one compound is administered in oraldosage form and is administered concurrently with consumption of food.In another embodiment, the at least one compound of Formulae I-XXVI isadministered in oral dosage form and is administered up to ninetyminutes after consumption of food. In another embodiment, the at leastone compound of Formulae I-XXVI is administered in oral dosage form andis administered up to thirty minutes before or up to thirty minutesafter consumption of food.

Preferably, the at least one compound is administered in combinationwith a high-fat meal. Although not required, and any type of food (highfat or low fat) is thought to aid absorption of the compounds of thepresent invention, a high-fat meal may provide additional improvedabsorption as compared to administration of the compounds with lower fatmeals. The term “food” is to be considered to have the ordinary meaningas is commonly understood in the society and community in general, withnon-limiting examples being low fat, high fat, non-fat, snack, solidmaterial, liquid material, high solid, low solid and the like. AS usedherein, “high fat” means food in which over about 30% of the caloriesare provided by fat. As will be understood by one skilled in the art, anincrease in bioavailability will occur in a dose dependent fashion, sothat any amount of food will provide at least some improvement, ascompared to administration with no food. Accordingly, administration ofthe drug in combination with food having at least about 50-100 caloriesup to about 1,000 calories can provide improved bioavailability.

Optionally, the at least one compound of Formulae I-XXVI is administeredin combination with a pharmaceutical selected from the group consistingof interferon alpha-2a, pegylated interferon alpha-2a, interferonalpha-2b pegylated interferon alpha-2b, interferon alphacon-1, andribavirin.

Also optionally, the at least one compound of Formulae I-XXVI isadministered in combination with at least one antiviral agent which isdifferent from the compound of Formulae I-XXVI and/or animmunomodulatory agent.

As used herein, the term “in combination with” means that a treatmentregimen incorporating additional pharmaceuticals, antiviral agentsand/or immunomodulatory agents is used in combination withadministration of the protease inhibitor. Each additional pharmaceuticalor agent is administered according to an optimal regimen determined foreach pharmaceutical or agent. For example, interferon or peglyatedinterferon is usually administered once per week. Typically, these otherpharmaceuticals or agents are administered in dosage forms separate fromthe protease inhibitor, although a combined dosage form, whereappropriate, is also within the scope of the present invention.

Suitable compounds of formula I are disclosed in PCT Internationalpublication WO03/062265 published Jul. 31, 2003. Non-limiting examplesof certain compounds disclosed in this publication include:

or a pharmaceutically acceptable salt, solvate or ester thereof.

In one embodiment, the HCV protease inhibitor is selected from the groupconsisting of

and pharmaceutically acceptable salts or solvates thereof.

The compound of formula Ia has recently been separated into itsisomer/diastereomers of Formulas Ib and Ic. In one embodiment, the HCVprotease inhibitor is selected from the group consisting of the compoundof Formula Ic and pharmaceutically acceptable salts or solvates thereofas a potent inhibitor of HCV NS3 serine protease.

The chemical name of the compound of Formula Ic is(1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide.

Processes for making compounds of Formula I are disclosed in U.S. PatentPublication Nos. 2005/0059648, 2005/0020689 and 2005/0059800,incorporated by reference herein.

Non-limiting examples of suitable compounds of formula II and methods ofmaking the same are disclosed in WO02/08256 and in U.S. Pat. No.6,800,434, at col. 5 through col. 247, incorporated herein by reference.

Non-limiting examples of suitable compounds of formula III and methodsof making the same are disclosed in International Patent PublicationWO02/08187 and in U.S. Patent Publication 2002/0160962 at page 3,paragraph 22 through page 132, incorporated herein by reference.

Non-limiting examples of suitable compounds of formula IV and methods ofmaking the same are disclosed in International Patent PublicationWO03/062228 and in U.S. Patent Publication 2003/0207861 at page 3,paragraph 25 through page 26, incorporated herein by reference.

Non-limiting examples of suitable compounds of formula V and methods ofmaking the same are disclosed in U.S. patent application Ser. No.10/948,367 filed Sep. 23, 2004, and the preparation of the compounds aredetailed in the experimental section of this application set forthhereinbelow.

Non-limiting examples of suitable compounds of formula VI and methods ofmaking the same are disclosed in U.S. Patent Publication Ser. No.2005/0085425 at page 3, paragraph 0023 through page 139, incorporatedherein by reference.

Compounds of formula VII-IX are disclosed in U.S. patent applicationSer. No. 10/993,394 filed Nov. 19, 2004, and the preparation of thecompounds are detailed in the experimental section of this applicationset forth hereinbelow.

Non-limiting examples of certain compounds of formula VII disclosed inU.S. patent application Ser. No. 10/993,394 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Nonlimiting examples of certain compounds of formula VIII disclosed inU.S. patent application Ser. No. 10/993,394 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Nonlimiting examples of certain compounds of formula IX disclosed inU.S. patent application Ser. No. 10/993,394 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula X are disclosed in U.S. patent application Ser. No.11/065,572 filed Feb. 24, 2005 and the preparation of the compounds aredetailed in the experimental section of this application set forthhereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. patentapplication Ser. No. 11/065,572 filed Feb. 24, 2005 are:

Compounds of formula XI are disclosed in U.S. application Ser. No.11/065,509 filed Feb. 24, 2005. The preparation of these compounds isdisclosed in the experimental section of this application set forthhereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. applicationSer. No. 11/065,509 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula XII are disclosed in U.S. patent application Ser.No. 11/065,531 filed Feb. 24, 2005. The preparation of these compoundsis disclosed in the experimental section of this application set forthhereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. patentapplication Ser. No. 11/065,531 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula XIII are disclosed in U.S. patent application Ser.No. 11/065,647 filed Feb. 24, 2005. The preparation of these compoundsis disclosed in the experimental section of this application set forthhereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. patentapplication Ser. No. 11/065,647 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula XIV are disclosed in U.S. patent application Ser.No. 11/064,673 filed Feb. 24, 2005. The preparation of these compoundsis disclosed in the experimental section of this application set forthhereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. patentapplication Ser. No. 11/064,673 are:

pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula XV are disclosed in U.S. patent application Ser.No. 11/007,910 filed Dec. 9, 2004. The preparation of these compounds isdisclosed in the experimental section of this application set forthhereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. patentapplication Ser. No. 11/007,910 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula XVI are disclosed in U.S. patent application Ser.No. 11/064,757 filed Feb. 24, 2005. The preparation of these compoundsis disclosed in the experimental section of this application set forthhereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. patentapplication Ser. No. 11/064,757 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula XVII are disclosed in U.S. patent application Ser.No. 11/064,574 filed Feb. 24, 2005. The preparation of these compoundsis disclosed in the experimental section of this application set forthhereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. patentapplication Ser. No. 11/064,574 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula XVIII are disclosed in U.S. Provisional PatentApplication Ser. No. 60/605,234 filed Aug. 27, 2004. The preparation ofthese compounds is disclosed in the experimental section of thisapplication set forth hereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. ProvisionalPatent Application Ser. No. 60/605,234 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula XIX are disclosed in U.S. Provisional PatentApplication Ser. No. 60/573,191 filed May 20, 2004. The preparation ofthese compounds is disclosed in the experimental section of thisapplication set forth hereinbelow.

Non-limiting examples of certain compounds disclosed in U.S. ProvisionalPatent Application Ser. No. 60/573,191 are:

or a pharmaceutically acceptable salt, solvate or ester thereof.

Compounds of formula (XX) have been disclosed in U.S. Pat. No. 6,767,991at col. 3, line 48 through col. 147, incorporated herein by reference.

Compounds of formula (XXI) have been disclosed in U.S. PatentPublication Nos. 2002/0016442, 2002/0037998 and U.S. Pat. Nos.6,268,207, 6,323,180 at col. 3, line 28 through col. 141, line 60, U.S.Pat. No. 6,329,379 at col. 3, line 28 through col. 147, line 27, U.S.Pat. No. 6,329,417 at col. 3, line 25 through col. 147, line 30, U.S.Pat. No. 6,410,531 at col. 3, line 28 through col. 141, U.S. Pat. No.6,534,523 at col. 3, line 34 through col. 139, line 29, and U.S. Pat.No. 6,420,380 at col. 3, line 28 through col. 141, line 65, eachincorporated herein by reference.

Compounds of formula (XXII) have been disclosed in PCT InternationalPatent Publication WO00/59929 published on Oct. 12, 2000, U.S. PatentPublication No. 2004/0002448 and U.S. Pat. No. 6,608,027 at col. 4through col. 137, incorporated herein by reference.

Compounds of formula (XXIII) have been disclosed in PCT InternationalPatent Publication WO02/18369 published on Mar. 7, 2002.

Compounds of formula (XXIV) have been disclosed U.S. Patent PublicationNos. 2002/0032175, 2004/0266731 and U.S. Pat. No. 6,265,380 at col. 3,line 35 through col. 121 and U.S. Pat. No. 6,617,309 at col. 3, line 40through col. 121, each incorporated herein by reference.

Compounds of formula (XXV) have been disclosed U.S. Pat. No. 5,866,684at col. 1 through col. 72 and U.S. Pat. No. 6,018,020 at col. 1 throughcol. 73, each incorporated herein by reference.

Compounds of formula (XXVI) have been disclosed in U.S. Pat. No.6,143,715 at col. 3, line 6 through col. 62, line 20, incorporatedherein by reference.

Isomers of the various compounds of the present invention (where theyexist), including enantiomers, stereoisomers, rotamers, tautomers andracemates are also contemplated as being part of this invention. Theinvention includes d and l isomers in both pure form and in admixture,including racemic mixtures. Isomers can be prepared using conventionaltechniques, either by reacting optically pure or optically enrichedstarting materials or by separating isomers of a compound of the presentinvention. Isomers may also include geometric isomers, e.g., when adouble bond is present. Polymorphous forms of the compounds of thepresent invention, whether crystalline or amorphous, also arecontemplated as being part of this invention. The (+) isomers of thepresent compounds are preferred compounds of the present invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare also within the scope of this invention.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in alternative tautomeric forms. All suchtautomeric forms of the present compounds are within the scope of theinvention. Unless otherwise indicated, the representation of eithertautomer is meant to include the other. For example, both isomers (1)and (2) are contemplated:

-   -   wherein R′ is H or C₁₋₆ unsubstituted alkyl.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N-ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N-(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

One or more compounds of the invention may also exist as, or optionallyconverted to, a solvate. Preparation of solvates is generally known.Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3),601-611 (2004) describe the preparation of the solvates of theantifungal fluconazole in ethyl acetate as well as from water. Similarpreparations of solvates, hemisolvate, hydrates and the like aredescribed by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). Atypical, non-limiting, process involves dissolving a compound in desiredamounts of the desired solvent (organic or water or mixtures thereof) ata higher than ambient temperature, and cooling the solution at a ratesufficient to form crystals which are then isolated by standard methods.Analytical techniques such as, for example I.R. spectroscopy, show thepresence of the solvent (or water) in the crystals as a solvate (orhydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of a compound or a composition of the presentinvention effective in inhibiting HCV protease and/or cathepsins, andthus producing the desired therapeutic, ameliorative, inhibitory orpreventative effect in a suitable subject.

The compounds of the present invention form salts that are also withinthe scope of this invention. Reference to a compound of the presentinvention herein is understood to include reference to salts, esters andsolvates thereof, unless otherwise indicated. The term “salt(s)”, asemployed herein, denotes acidic salts formed with inorganic and/ororganic acids, as well as basic salts formed with inorganic and/ororganic bases. In addition, when a compound of formula I contains both abasic moiety, such as, but not limited to a pyridine or imidazole, andan acidic moiety, such as, but not limited to a carboxylic acid,zwitterions (“inner salts”) may be formed and are included within theterm “salt(s)” as used herein. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred, althoughother salts are also useful. Salts of the compounds of the variousformulae of the present invention may be formed, for example, byreacting a compound of the present invention with an amount of acid orbase, such as an equivalent amount, in a medium such as one in which thesalt precipitates or in an aqueous medium followed by lyophilization.Acids (and bases) which are generally considered suitable for theformation of pharmaceutically useful salts from basic (or acidic)pharmaceutical compounds are discussed, for example, by S. Berge et al,Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, ThePractice of Medicinal Chemistry (1996), Academic Press, New York; in TheOrange Book (Food & Drug Administration, Washington, D.C. on theirwebsite); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l.Union of Pure and Applied Chemistry, pp. 330-331. These disclosures areincorporated herein by reference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates, sulfonates (such as those mentionedherein), tartarates, thiocyanates, toluenesulfonates (also known astosylates,) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides (e.g.methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention. All acid and basesalts, as well as esters and solvates, are considered equivalent to thefree forms of the corresponding compounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

In such esters, unless otherwise specified, any alkyl moiety presentpreferably contains from 1 to 18 carbon atoms, particularly from 1 to 6carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkylmoiety present in such esters preferably contains from 3 to 6 carbonatoms. Any aryl moiety present in such esters preferably comprises aphenyl group.

In another embodiment, this invention provides pharmaceuticalcompositions comprising the inventive peptides as an active ingredient.The pharmaceutical compositions generally additionally comprise apharmaceutically acceptable carrier diluent, excipient or carrier(collectively referred to herein as carrier materials). Because of theirHCV inhibitory activity, such pharmaceutical compositions possessutility in treating hepatitis C and related disorders.

Another embodiment of the invention discloses the use of thepharmaceutical compositions disclosed above for treatment of diseasessuch as, for example, hepatitis C and the like. The method comprisesadministering a therapeutically effective amount of the inventivepharmaceutical composition to a patient having such a disease ordiseases and in need of such a treatment.

The nomenclature of Simmonds, P. et al. (“Classification of hepatitis Cvirus into six major genotypes and a series of subtypes by phylogeneticanalysis of the NS-5 region,” J. Gen. Virol., 74:2391-9, 1993) is widelyused and classifies isolates into six major genotypes, 1 through 6, withtwo or more related subtypes, e.g., 1a, 1b. Additional genotypes 7-10and 11 have been proposed, however the phylogenetic basis on which thisclassification is based has been questioned, and thus types 7, 8, 9 and11 isolates have been reassigned as type 6, and type 10 isolates as type3. (Lamballerie, X. et al., “Classification of hepatitis C variants insix major types based on analysis of the envelope 1 and nonstructural 5Bgenome regions and complete polyprotein sequences,” J. Gen. Virol.,78:45-51, 1997). The major genotypes have been defined as havingsequence similarities of between 55 and 72% (mean 64.5%), and subtypeswithin types as having 75%-86% similarity (mean 80%) when sequenced inthe NS-5 region. (Simmonds, P. et al., “Identification of genotypes ofhepatitis C by sequence comparisons in the core, E1 and NS-5 regions,”J. Gen. Virol., 75:1053-61, 1994).

In yet another embodiment, the compounds of the invention may be usedfor the treatment of HCV in humans in monotherapy mode or in acombination therapy (e.g., dual combination, triple combination etc.)mode such as, for example, in combination with antiviral and/orimmunomodulatory agents. Examples of such antiviral and/orimmunomodulatory agents include Ribavirin (from Schering-PloughCorporation, Madison, N.J.) and Levovirin™ (from ICN Pharmaceuticals,Costa Mesa, Calif.), VP 50406™ (from Viropharma, Incorporated, Exton,Pa.), ISIS 14803™ (from ISIS Pharmaceuticals, Carlsbad, Calif.),Heptazyme™ (from Ribozyme Pharmaceuticals, Boulder, Colo.), VX 497™(from Vertex Pharmaceuticals, Cambridge, Mass.), Thymosin™ (fromSciClone Pharmaceuticals, San Mateo, Calif.), Maxamine™ (MaximPharmaceuticals, San Diego, Calif.), mycophenolate mofetil (fromHoffman-LaRoche, Nutley, N.J.), interferon (such as, for example,interferon-alpha, PEG-interferon alpha conjugates) and the like.“PEG-interferon alpha conjugates” are interferon alpha moleculescovalently attached to a PEG molecule. Illustrative PEG-interferon alphaconjugates include interferon alpha-2a (Roferon™, from Hoffman La-Roche,Nutley, N.J.) in the form of pegylated interferon alpha-2a (e.g., assold under the trade name Pegasys™), interferon alpha-2b (Intron™, fromSchering-Plough Corporation) in the form of pegylated interferonalpha-2b (e.g., as sold under the trade name PEG-Intron™), interferonalpha-2c (Berofor Alpha™, from Boehringer Ingelheim, Ingelheim, Germany)or consensus interferon as defined by determination of a consensussequence of naturally occurring interferon alphas (Infergen™, fromAmgen, Thousand Oaks, Calif.).

The compound of Formulae I-XXVI can be administered in combination withinterferon alpha, PEG-interferon alpha conjugates or consensusinterferon concurrently or consecutively at recommended dosages for theduration of HCV treatment in accordance with the methods of the presentinvention. The commercially available forms of interferon alpha includeinterferon alpha 2a and interferon alpha 2b and also pegylated forms ofboth aforementioned interferon alphas. The recommended dosage ofINTRON-A interferon alpha 2b (commercially available fromSchering-Plough Corp.) as administered by subcutaneous injection at 3MIU (12 mcg)/0.5 mL/TIW is for 24 weeks or 48 weeks for first timetreatment. The recommended dosage of PEG-INTRON interferon alpha 2bpegylated (commercially available from Schering-Plough Corp.) asadministered by subcutaneous injection at 1.5 mcg/kg/week, within arange of 40 to 150 mcg/week, is for at least 24 weeks. The recommendeddosage of ROFERON A interferon alpha 2a (commercially available fromHoffmann-La Roche) as administered by subcutaneous or intramuscularinjection at 3 MIU (11.1 mcg/mL)/TIW is for at least 48 to 52 weeks, oralternatively 6 MIU/TIW for 12 weeks followed by 3 MIU/TIW for 36 weeks.The recommended dosage of PEGASUS interferon alpha 2a pegylated(commercially available from Hoffmann-La Roche) as administered bysubcutaneous injection at 180 mcg/1 mL or 180 mcg/0.5 mL is once a weekfor at least 24 weeks. The recommended dosage of INFERGEN interferonalphacon-1 (commercially available from Amgen) as administered bysubcutaneous injection at 9 mcg/TIW is for 24 weeks for first timetreatment and up to 15 mcg/TIW for 24 weeks for non-responsive orrelapse treatment. Optionally, Ribavirin, a synthetic nucleosideanalogue with activity against a broad spectrum of viruses includingHCV, can be included in combination with the interferon and the compoundof Formulae I-XXVI. The recommended dosage of ribavirin is in a rangefrom 600 to 1400 mg per day for at least 24 weeks (commerciallyavailable as REBETOL ribavirin from Schering-Plough or COPEGUS ribavirinfrom Hoffmann-La Roche).

In one embodiment, the compounds of the invention can be used to treatcellular proliferation diseases. Such cellular proliferation diseasestates which can be treated by the compounds, compositions and methodsprovided herein include, but are not limited to, cancer (furtherdiscussed below), hyperplasia, cardiac hypertrophy, autoimmune diseases,fungal disorders, arthritis, graft rejection, inflammatory boweldisease, immune disorders, inflammation, cellular proliferation inducedafter medical procedures, including, but not limited to, surgery,angioplasty, and the like. Treatment includes inhibiting cellularproliferation. It is appreciated that in some cases the cells may not bein a hyper- or hypoproliferation state (abnormal state) and stillrequire treatment. For example, during wound healing, the cells may beproliferating “normally”, but proliferation enhancement may be desired.Thus, in one embodiment, the invention herein includes application tocells or subjects afflicted or subject to impending affliction with anyone of these disorders or states.

The methods provided herein are particularly useful for the treatment ofcancer including solid tumors such as skin, breast, brain, colon, gallbladder, thyroid, cervical carcinomas, testicular carcinomas, etc. Moreparticularly, cancers that may be treated by the compounds, compositionsand methods of the invention include, but are not limited to:

Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

Lung: bronchogenic carcinoma (squamous cell, undifferentiated smallcell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma;

Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma);

Genitourinarv tract: kidney (adenocarcinoma, Wilm's tumor(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);

Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors;

Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma (pinealoma), glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma);

Gynecological: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma(serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma);

Hematologic: blood (myeloid leukemia (acute and chronic), acutelymphoblastic leukemia, acute and chronic lymphocytic leukemia,myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignantlymphoma), B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma,Burkett's lymphoma, promyelocytic leukemia;

Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma,Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis;

Adrenal glands: neuroblastoma; and

Other tumors: including xenoderoma pigmentosum, keratoctanthoma andthyroid follicular cancer.

As used herein, treatment of cancer includes treatment of cancerouscells, including cells afflicted by any one of the above-identifiedconditions.

The compounds of the present invention may also be useful in thechemoprevention of cancer. Chemoprevention is defined as inhibiting thedevelopment of invasive cancer by either blocking the initiatingmutagenic event or by blocking the progression of pre-malignant cellsthat have already suffered an insult or inhibiting tumor relapse.

The compounds of the present invention may also be useful in inhibitingtumor angiogenesis and metastasis.

The compounds of the present invention may also be useful as antifungalagents, by modulating the activity of the fungal members of the bimCkinesin subgroup, as is described in U.S. Pat. No. 6,284,480.

The present compounds are also useful in combination with one or moreother known therapeutic agents and anti-cancer agents. Combinations ofthe present compounds with other anti-cancer or chemotherapeutic agentsare within the scope of the invention. Examples of such agents can befound in Cancer Principles and Practice of Oncology by V. T. Devita andS. Hellman (editors), 6^(th) edition (Feb. 15, 2001), LippincottWilliams & Wilkins Publishers. A person of ordinary skill in the artwould be able to discern which combinations of agents would be usefulbased on the particular characteristics of the drugs and the cancerinvolved. Such anti-cancer agents include, but are not limited to, thefollowing: estrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxic/cytostatic agents,antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoAreductase inhibitors and other angiogenesis inhibitors, inhibitors ofcell proliferation and survival signaling, apoptosis inducing agents andagents that interfere with cell cycle checkpoints. The present compoundsare also useful when co-administered with radiation therapy.

The phrase “estrogen receptor modulators” refers to compounds thatinterfere with or inhibit the binding of estrogen to the receptor,regardless of mechanism. Examples of estrogen receptor modulatorsinclude, but are not limited to, tamoxifen, raloxifene, idoxifene,LY353381, LY117081, toremifene, fulvestrant,4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-ydrazone, aid SH646.

The phrase “androgen receptor modulators” refers to compounds whichinterfere or inhibit the binding of androgens to the receptor,regardless of mechanism. Examples of androgen receptor modulatorsinclude finasteride and other 5α-reductase inhibitors, nilutamide,flutamide, bicalutamide, liarozole, and abiraterone acetate.

The phrase “retinoid receptor modulators” refers to compounds whichinterfere or inhibit the binding of retinoids to the receptor,regardless of mechanism. Examples of such retinoid receptor modulatorsinclude bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoicacid, a difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

The phrase “cytotoxic/cytostatic agents” refer to compounds which causecell death or inhibit cell proliferation primarily by interferingdirectly with the cell's functioning or inhibit or interfere with cellmycosis, including alkylating agents, tumor necrosis factors,intercalators, hypoxia activatable compounds, microtubuleinhibitors/microtubule-stabilizing agents, inhibitors of mitotickinesins, inhibitors of kinases involved in mitotic progression,antimetabolites; biological response modifiers; hormonal/anti-hormonaltherapeutic agents, haematopoietic growth factors, monoclonal antibodytargeted therapeutic agents, monoclonal antibody therapeutics,topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligaseinhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine,prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin,oxaliplatin, temozolomide (TEMODARM™ from Schering-Plough Corporation,Kenilworth, N.J.), cyclophosphamide, heptaplatin, estramustine,improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride,pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, doxorubicin,irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum,benzylguanine, glufosfamide, GPX100,(trans,trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride,diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deansino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755,4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunombicin (see WO00/50032), methoxtrexate, gemcitabine, and mixture thereof.

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteasome inhibitors include, but are not limited to,lactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude paclitaxel, vindesine sulfate,3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxel, rhizoxin,dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881,BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,dimesna, and camptostar.

Other useful anti-cancer agents that can be used in combination with thepresent compounds include thymidilate synthase inhibitors, such as5-fluorouracil.

In one embodiment, inhibitors of mitotic kinesins include, but are notlimited to, inhibitors of KSP, inhibitors of MKLP1, inhibitors ofCENP-E, inhibitors of MCAK, inhibitors of Kifl4, inhibitors of Mphosphland inhibitors of Rab6-KIFL.

The phrase “inhibitors of kinases involved in mitotic progression”include, but are not limited to, inhibitors of aurora kinase, inhibitorsof Polo-like kinases (PLK) (in particular inhibitors of PLK-1),inhibitors of bub-1 and inhibitors of bub-R1.

The phrase “antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,neizarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-flurouracil, alanosine,1′-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N-4-palmitoyl-1-B-D-arabino furanosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

Examples of monoclonal antibody therapeutics useful for treating cancerinclude Erbitux (Cetuximab).

The phrase “HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin,simvastatin (ZOCOR®), pravastatin (PRAVACHOL®), fluvastatin andatorvastatin (LIPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893,5,489,691 and 5,342,952). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefore the use of such salts, esters, openacid and lactone forms is included in the scope of this invention.

The phrase “prenyl-protein transferase inhibitor” refers to a compoundwhich inhibits any one or any combination of the prenyl-proteintransferase enzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

Examples of prenyl-protein transferase inhibitors can be found in thefollowing publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510,5,589,485, 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604181, European Patent Publ. 0696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO, 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European ofCancer, Vol. 35, No. 9, pp. 1394-1401(1999).

Examples of farnesyl protein transferase inhibitors include SARASAR™(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoehtyl]-1-piperidinecarboxamidefrom Schering-Plough Corporation, Kenilworth, N.J.), tipifarnib(Zarnestra® or R115777 from Janssen Pharmaceuticals), L778,123 (afarnesyl protein transferase inhibitor from Merck & Company, WhitehouseStation, N.J.), BMS 214662 (a farnesyl protein transferase inhibitorfrom Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.).

The phrase “angiogenesis inhibitors” refers to compounds that inhibitthe formation of new blood vessels, regardless of mechanism. Examples ofangiogenesis inhibitors include, but are not limited to, tyrosine kinaseinhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1(VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived,fibroblast-derived, or platelet derived growth factors, MMP (matrixmetalloprotease) inhibitors, integrin blockers, interferon-α (forexample Intron and Peg-Intron), interleukin-12, pentosan polysulfate,cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories(NSAIDs) like aspirin and ibuprofen as well as selectivecyclooxygenase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89,p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol.108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994); FEBS Letters,Vol. 372, p. 83 (1995); Clin. Orthop. Vol. 313, p. 76 (1995); J. Mol.Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105(1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705(1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol.274, p. 9116 (1999)), steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betamethasone), carboxyamidotriazole,combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (seeFernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodiesto VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999);Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). Examples of TAFIa inhibitors have been described in PCTPublication WO 03/013,526.

The phrase “agents that interfere with cell cycle checkpoints” refers tocompounds that inhibit protein kinases that transduce cell cyclecheckpoint signals, thereby sensitizing the cancer cell to DNA damagingagents. Such agents include inhibitors of ATR, ATM, the Chk1 and Chk2kinases and cdk and cdc kinase inhibitors and are specificallyexemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel)and BMS-387032.

The phrase “inhibitors of cell proliferation and survival signalingpathway” refers to agents that inhibit cell surface receptors and signaltransduction cascades downstream of those surface receptors. Such agentsinclude inhibitors of EGFR (for example gefitinib and erlotinib),antibodies to EGFR (for example C225), inhibitors of ERB-2 (for exampletrastuzumab), inhibitors of IGFR, inhibitors of cytokine receptors,inhibitors of MET, inhibitors of PI3K (for example LY294002),serine/threonine kinases (including but not limited to inhibitors of Aktsuch as described in WO 02/083064, WO 02/083139, WO 02/083140 and WO02/083138), inhibitors of Raf kinase (for example BAY-43-9006),inhibitors of MEEK (for example CI-1040 and PD-098059), inhibitors ofmTOR (for example Wyeth CCI-779), and inhibitors of C-abl kinase (forexample GLEEVEC™, Novartis Pharmaceuticals). Such agents include smallmolecule inhibitor compounds and antibody antagonists.

The phrase “apoptosis inducing agents” includes activators of TNFreceptor family members (including the TRAIL receptors).

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1evaluated by cell or microsomal assays. Inhibitors of COX-2 that areparticularly useful in the instant method of treatment are:3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5 pyridinyl)pyridine; ora pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to, parecoxib, CELEBREX® and BEXTRA® or a pharmaceuticallyacceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpimase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(ν)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the α_(ν)β₅ integrin,to compounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(ν)β₃ integrin and the α_(ν)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(ν)β₆,α_(ν)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(ν)β₃, α_(ν)β₅, α_(ν)β₆, α_(ν)β₈,α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, STI571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571 A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are alsoencompassed in the instant methods. For example, combinations of thepresent compounds with PPAR-γ (i.e., PPAR-gamma) agonists and PPAR-δ(i.e., PPAR-delta) agonists are useful in the treatment of certainmalingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisomeproliferator-activated receptors γ and δ. The expression of PPAR-γ onendothelial cells and its involvement in angiogenesis has been reportedin the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J.Biol. Chem. 1999; 274:9116-9121; Invest. Ophthalmol Vis. Sci. 2000;41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibitthe angiogenic response to VEGF in vitro; both troglitazone androsiglitazone maleate inhibit the development of retinalneovascularization in mice (Arch. Ophthamol. 2001; 119:709-717).Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are notlimited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone,rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate,GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544,NN2344, KRP297, NP0110, DRF4158, NN622, G1262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid, and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid.

In one embodiment, useful anti-cancer (also known as anti-neoplastic)agents that can be used in combination with the present compoundsinclude, but are not limited, to Uracil mustard, Chlormethine,Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin (ELOXATIN™ from Sanofi-Synthelabo Pharmaeuticals, France),Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methyl prednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, doxorubicin (adriamycin), cyclophosphamide(cytoxan), gemcitabine, interferons, pegylated interferons, Erbitux andmixtures thereof.

Another embodiment of the present invention is the use of the presentcompounds in combination with gene therapy for the treatment of cancer.For an overview of genetic strategies to treating cancer, see Hall et al(Am J Hum Genet 61:785-789,1997) and Kufe et al (Cancer Medicine, 5thEd, pp 876-889, B C Decker, Hamilton 2000). Gene therapy can be used todeliver any tumor suppressing gene. Examples of such genes include, butare not limited to, p53, which can be delivered via recombinantvirus-mediated gene transfer (see U.S. Pat. No. 6,069,134, for example),a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of a uPA/uPARAntagonist Suppresses Angiogenesis-Dependent Tumor Growth andDissemination in Mice,” Gene Therapy, August 1998; 5(8): 1105-13), andinterferon gamma (J Immunol 2000; 164:217-222).

The present compounds can also be administered in combination with oneor more inhibitor of inherent multidrug resistance (MDR), in particularMDR associated with high levels of expression of transporter proteins.Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such asLY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).

The present compounds can also be employed in conjunction with one ormore anti-emetic agents to treat nausea or emesis, including acute,delayed, late-phase, and anticipatory emesis, which may result from theuse of a compound of the present invention, alone or with radiationtherapy. For the prevention or treatment of emesis, a compound of thepresent invention may be used in conjunction with one or more otheranti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3receptor, antagonists, such as ondansetron, granisetron, tropisetron,and zatisetron, GABAB receptor agonists, such as baclofen, acorticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort,Nasalide, Preferid, Benecorten or those as described in U.S. Pat. Nos.2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359,3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines(for example prochlorperazine, fluphenazine, thioridazine andmesoridazine), metoclopramide or dronabinol. In one embodiment, ananti-emesis agent selected from a neurokinin-1 receptor antagonist, a5HT3 receptor antagonist and a corticosteroid is administered as anadjuvant for the treatment or prevention of emesis that may result uponadministration of the present compounds.

Examples of neurokinin-1 receptor antagonists that can be used inconjunction with the present compounds are described in U.S. Pat. Nos.5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270,5,494,926, 5,496,833, 5,637,699, and 5,719,147, content of which areincorporated herein by reference. In an embodiment, the neurokinin-1receptor antagonist for use in conjunction with the compounds of thepresent invention is selected from:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the present invention may also be administered with one ormore immunologic-enhancing drug, such as for example, levamisole,isoprinosine and Zadaxin.

Thus, the present invention encompasses the use of the present compounds(for example, for treating or preventing cellular proliferativediseases) in combination with a second compound selected from: anestrogen receptor modulator, an androgen receptor modulator, retinoidreceptor modulator, a cytotoxic/cytostatic agent, an antiproliferativeagent, a prenyl-protein transferase inhibitor, an HMG-CoA reductaseinhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δagonist, an inhibitor of inherent multidrug resistance, an anti-emeticagent, an immunologic-enhancing drug, an inhibitor of cell proliferationand survival signaling, an agent that interfers with a cell cyclecheckpoint, and an apoptosis inducing agent.

In one embodiment, the present invention emcompasses the composition anduse of the present compounds in combination with a second compoundselected from: a cytostatic agent, a cytotoxic agent, taxanes, atopoisomerase II inhibitor, a topoisomerase I inhibitor, a tubulininteracting agent, hormonal agent, a thymidilate synthase inhibitors,anti-metabolites, an alkylating agent, a farnesyl protein transferaseinhibitor, a signal transduction inhibitor, an EGFR kinase inhibitor, anantibody to EGFR, a C-abl kinase inhibitor, hormonal therapycombinations, and aromatase combinations.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

In one embodiment, the angiogenesis inhibitor to be used as the secondcompound is selected from a tyrosine kinase inhibitor, an inhibitor ofepidermal-derived growth factor, an inhibitor of fibroblast-derivedgrowth factor, an inhibitor of platelet derived growth factor, an MW(matrix metalloprotease) inhibitor, an integrin blocker, interferon-α,interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor,carboxyamidotriazole, combretastatin A-4, squalamine,6-(O-chloroacetylcarbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, or an antibody to VEGF. In an embodiment, the estrogenreceptor modulator is tamoxifen or raloxifene.

Also included in the present invention is a method of treating cancercomprising administering a therapeutically effective amount of at leastone compound of the present invention in combination with radiationtherapy and at least one compound selected from: an estrogen receptormodulator, an androgen receptor modulator, retinoid receptor modulator,a cytotoxic/cytostatic agent, an antiproliferative agent, aprenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, anangiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an inhibitorof inherent multidrug resistance, an anti-emetic agent, animmunologic-enhancing drag, an inhibitor of cell proliferation andsurvival signaling, an agent that interfers with a cell cyclecheckpoint, and an apoptosis inducing agent.

Yet another embodiment of the invention is a method of treating cancercomprising administering a therapeutically effective amount of at leastone compound of the present invention in combination with paclitaxel ortrastuzumab.

The present invention also includes a pharmaceutical composition usefulfor treating or preventing the various disease states mentioned hereincellular proliferation diseases (such as cancer, hyperplasia, cardiachypertrophy, autoimmune diseases, fungal disorders, arthritis, graftrejection, inflammatory bowel disease, immune disorders, inflammation,and cellular proliferation induced after medical procedures) thatcomprises a therapeutically effective amount of at least one compound ofthe present invention and at least one compound selected from: anestrogen receptor modulator, an androgen receptor modulator, a retinoidreceptor modulator, a cytotoxic/cytostatic agent, an antiproliferativeagent, a prenyl-protein transferase inhibitor, an HMG-CoA reductaseinhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δagonist, an inhibitor of cell proliferation and survival signaling, anagent that interfers with a cell cycle checkpoint, and an apoptosisinducing agent.

When the disease being treated by the cathepsin inhibitor compounds ofthe present invention is inflammatory disease, an embodiment of thepresent invention comprises administering: (a) a therapeuticallyeffective amount of at least one compound of the present cathepsininhibitors (e.g., a compound according to Formula I-XXVII) or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one medicament selected from the groupconsisting of: disease modifying antirheumatic drugs; nonsteroidalanti-inflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors;immunosuppressives (non-limiting examples include methotrexate,cyclosporin, FK506); steroids; PDE IV inhibitors, anti-TNF-α compounds,TNF-alpha-convertase inhibitors, cytokine inhibitors, MMP inhibitors,glucocorticoids, chemokine inhibitors, CB2-selective inhibitors, p38inhibitors, biological response modifiers; anti-inflammatory agents andtherapeutics.

Another embodiment of the present invention is directed to a method ofinhibiting or blocking T-cell mediated chemotaxis in a patient in needof such treatment the method comprising administering to the patient atherapeutically effective amount of at least one compound of the presentcathepsin inhibitors (e.g., a compound according to formula I-XXVII) ora pharmaceutically acceptable salt, solvate or ester thereof.

Another embodiment of this invention is directed to a method of treatinginflammatory bowel disease in a patient in need of such treatmentcomprising administering to the patient a therapeutically effectiveamount of at least one compound according to the present cathepsininhibitors or a pharmaceutically acceptable salt, solvate or esterthereof.

Another embodiment of this invention is directed to a method of treatingor preventing graft rejection in a patient in need of such treatmentcomprising administering to the patient a therapeutically effectiveamount of at least one compound according to the present cathepsininhibitors, or a pharmaceutically acceptable salt, solvate or esterthereof.

Another embodiment of this invention is directed to a method comprisingadministering to the patient a therapeutically effective amount of: (a)at least one compound according to the present cathepsin inhibitors, ora pharmaceutically acceptable salt, solvate or ester thereofconcurrently or sequentially with (b) at least one compound selectedfrom the group consisting of: cyclosporine A, FK-506, FTY720,beta-Interferon, rapamycin, mycophenolate, prednisolone, azathioprine,cyclophosphamide and an antilymphocyte globulin.

Another embodiment of this invention is directed to a method of treatingmultiple sclerosis in a patient in need of such treatment the methodcomprising administering to the patient a therapeutically effectiveamount of: (a) at least one compound according to the present cathepsininhibitors, or a pharmaceutically acceptable salt, solvate or esterthereof concurrently or sequentially with (b) at least one compoundselected from the group consisting of: beta-interferon, glatirameracetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone,VLA-4 inhibitors and/or CB2-selective inhibitors.

Another embodiment of this invention is directed to a method of treatingmultiple sclerosis in a patient in need of such treatment the methodcomprising administering to the patient a therapeutically effectiveamount of: a) at least one compound according to the present cathepsininhibitors, or a pharmaceutically acceptable salt, solvate or esterthereof concurrently or sequentially with (b) at least one compoundselected from the group consisting of: methotrexate, cyclosporin,leflunimide, sulfasalazine, β-methasone, β-interferon, glatirameracetate, prednisone, etonercept, and infliximab.

Another embodiment of this invention is directed to a method of treatingrheumatoid arthritis in a patient in need of such treatment the methodcomprising administering to the patient a therapeutically effectiveamount of: (a) at least one compound according to the present cathepsininhibitors or a pharmaceutically acceptable salt, solvate or esterthereof concurrently or sequentially with (b) at least one compoundselected from the group consisting of: COX-2 inhibitors, COX inhibitors,immunosuppressives, steroids, PDE IV inhibitors, anti-TNF-α compounds,MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selectiveinhibitors, caspase (ICE) inhibitors and other classes of compoundsindicated for the treatment of rheumatoid arthritis.

Another embodiment of this invention is directed to a method of treatingpsoriasis in a patient in need of such treatment the method comprisingadministering to the patient a therapeutically effective amount of: a)at least one compound according to present cathepsin inhibitors, or apharmaceutically acceptable salt, solvate or ester thereof concurrentlyor sequentially with (b) at least one compound selected from the groupconsisting of: immunosuppressives, steroids, and anti-TNF-α compounds.

Another embodiment of this invention is directed to a method of treatinga disease selected from the group consisting of: inflammatory disease,rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease,graft rejection, psoriasis, fixed drug eruptions, cutaneous delayed-typehypersensitivity responses, tuberculoid leprosy, type I diabetes, viralmeningitis and tumors in a patient in need of such treatment, suchmethod comprising administering to the patient an effective amount of atleast one compound according to present cathepsin inhibitors, or apharmaceutically acceptable salt, solvate or ester thereof.

Another embodiment of this invention is directed to a method of treatinga disease selected from the group consisting of inflammatory disease,rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease,graft rejection, psoriasis, fixed drug eruptions, cutaneous delayed-typehypersensitivity responses, tuberculoid leprosy and cancer in a patientin need of such treatment, such method comprising administering to thepatient an effective amount of at least one compound according to thepresent cathepsin inhibitors, or a pharmaceutically acceptable salt,solvate or ester thereof.

Another embodiment of this invention is directed to a method of treatinga disease selected from the group consisting of inflammatory disease,rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease,graft rejection, psoriasis, fixed drug eruptions, cutaneous delayed-typehypersensitivity responses and tuberculoid leprosy, type I diabetes,viral meningitis and cancer in a patient in need of such treatment, suchmethod comprising administering to the patient an effective amount of(a) at least one compound according to the present cathepsin inhibitors,or a pharmaceutically acceptable salt, solvate or ester thereofconcurrently or sequentially with (b) at least one medicament selectedfrom the group consisting of: disease modifying antirheumatic drugs;nonsteroidal anti-inflammatory drugs; COX-2 selective inhibitors; COX-1inhibitors; immunosuppressives; steroids; PDE IV inhibitors, anti-TNF-αcompounds, MMP inhibitors, glucocorticoids, chemokine inhibitors,CB2-selective inhibitors, biological response modifiers;anti-inflammatory agents and therapeutics.

When the present invention involves a method of treating acardiovascular disease, in addition to administering the cathepsininhibitors of the present invention, the method further comprisesadministering to the subject in need one or more pharmacological ortherapeutic agents or drugs such as cholesterol biosynthesis inhibitorsand/or lipid-lowering agents discussed below.

Non-limiting examples of cholesterol biosynthesis inhibitors for use inthe compositions, therapeutic combinations and methods of the presentinvention include competitive inhibitors of HMG CoA reductase, therate-limiting step in cholesterol biosynthesis, squalene synthaseinhibitors, squalene epoxidase inhibitors and mixtures thereof.Non-limiting examples of suitable HMG CoA reductase inhibitors includestatins such as lovastatin (for example MEVACOR® which is available fromMerck & Co.), pravastatin (for example PRAVACHOL® which is availablefrom Bristol Meyers Squibb), fluvastatin, simvastatin (for exampleZOCOR® which is available from Merck & Co.), atorvastatin, cerivastatin,rosuvastatin, rivastatin (sodium7-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl)-3,5-dihydroxy-6-heptanoate,CI-981 and pitavastatin (such as NK-104 of Negma Kowa of Japan); HMG CoAsynthetase inhibitors, for example L-659,699((E,E)-11-[3′R-(hydroxy-methyl)-4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid); squalene synthesis inhibitors, for example squalestatin 1; andsqualene epoxidase inhibitors, for example, NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride) and other sterol biosynthesis inhibitors such as DMP-565.Preferred HMG CoA reductase inhibitors include lovastatin, pravastatinand simvastatin.

In another embodiment, the method of treatment comprises administeringthe present cathepsin inhibitors in combination with one or morecardiovascular agents and one or more cholesterol biosynthesisinhibitors.

In another alternative embodiment, the method treatment of the presentinvention can further comprise administering nicotinic acid (niacin)and/or derivatives thereof coadministered with or in combination withthe cardiovascular agent(s) and sterol absorption inhibitor(s) discussedabove.

As used herein, “nicotinic acid derivative” means a compound comprisinga pyridine-3-carboxylate structure or a pyrazine-2-carboxylatestructure, including acid forms, salts, esters, zwitterions andtautomers, where available. Examples of nicotinic acid derivativesinclude niceritrol, nicofuranose and acipimox (5-methylpyrazine-2-carboxylic acid 4-oxide). Nicotinic acid and its derivativesinhibit hepatic production of VLDL and its metabolite LDL and increasesHDL and apo A-1 levels. An example of a suitable nicotinic acid productis NIASPAN® (niacin extended-release tablets) which are available fromKos.

In another alternative embodiment, the method of treatment of thepresent invention can further comprise administering one or moreAcylCoA:Cholesterol O-acyltransferase (“ACAT”) Inhibitors, which canreduce LDL and VLDL levels, coadministered with or in combination withthe cardiovascular agent(s) and sterol absorption inhibitor(s) discussedabove. ACAT is an enzyme responsible for esterifying excessintracellular cholesterol and may reduce the synthesis of VLDL, which isa product of cholesterol esterification, and overproduction of apoB-100-containing lipoproteins.

Non-limiting examples of useful ACAT inhibitors include avasimibe([[2,4,6-tris(1-methylethyl)phenyl]acetyl]sulfamic acid,2,6-bis(1-methylethyl)phenyl ester, formerly known as CI-1011), HL-004,lecimibide (DuP-128) and CL-277082(N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-heptylurea).See P. Chang et al., “Current, New and Future Treatments inDyslipidaemia and Atherosclerosis”, Drugs 2000 July; 60(1); 55-93, whichis incorporated by reference herein.

In another alternative embodiment, the method of treatment of thepresent invention can further comprise administering probucol orderivatives thereof (such as AGI-1067 and other derivatives disclosed inU.S. Pat. Nos. 6,121,319 and 6,147,250), which can reduce LDL levels,coadministered with or in combination with the cardiovascular agent(s)and sterol absorption inhibitor(s) discussed above.

In another alternative embodiment, the method of treatment of thepresent invention can further comprise administering fish oil, whichcontains Omega 3 fatty acids (3-PUFA), which can reduce VLDL andtriglyceride levels, coadministered with or in combination with thecardiovascular agent(s) and sterol absorption inhibitor(s) discussedabove. Generally, a total daily dosage of fish oil or Omega 3 fattyacids can range from about 1 to about 30 grams per day in single or 24divided doses.

In another alternative embodiment, the method of treatment of thepresent invention can further comprise administering natural watersoluble fibers, such as psyllium, guar, oat and pectin, which can reducecholesterol levels, coadministered with or in combination with thecardiovascular agent(s) and sterol absorption inhibitor(s) discussedabove. Generally, a total daily dosage of natural water soluble fiberscan range from about 0.1 to about 10 grams per day in single or 2-4divided doses.

In another alternative embodiment, the method of treatment of thepresent invention can further comprise administering plant sterols,plant stanols and/or fatty acid esters of plant stanols, such assitostanol ester used in BENECOL® margarine, which can reducecholesterol levels, coadministered with or in combination with thecardiovascular agent(s) and sterol absorption inhibitor(s) discussedabove. Generally, a total daily dosage of plant sterols, plant stanolsand/or fatty acid esters of plant stanols can range from about 0.5 toabout 20 grams per day in single or 24 divided doses.

In another alternative embodiment, the method of treatment of thepresent invention can further comprise administering antioxidants, suchas probucol, tocopherol, ascorbic acid, β-carotene and selenium, orvitamins such as vitamin B₆ or vitamin B₁₂, coadministered with or incombination with the cardiovascular agent(s) and sterol absorptioninhibitor(s) discussed above. Generally, a total daily dosage ofantioxidants or vitamins can range from about 0.05 to about 10 grams perday in single or 2-4 divided doses.

In another alternative embodiment, the method of treatment of thepresent invention can further comprise administering one or more bileacid sequestrants (insoluble anion exchange resins), coadministered withor in combination with the cardiovascular agents and sterol absorptioninhibitor(s) discussed above.

Bile acid sequestrants bind bile acids in the intestine, interruptingthe enterohepatic circulation of bile acids and causing an increase inthe faecal excretion of steroids. Use of bile acid sequestrants isdesirable because of their non-systemic mode of action. Bile acidsequestrants can lower intrahepatic cholesterol and promote thesynthesis of apo B/E (LDL) receptors which bind LDL from plasma tofurther reduce cholesterol levels in the blood.

Non-limiting examples of suitable bile acid sequestrants includecholestyramine (a styrene-divinylbenzene copolymer containing quaternaryammonium cationic groups capable of binding bile acids, such asQUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available fromBristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are availablefrom Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)-trimethylammoniumbromide) which are available from Sankyo), water soluble derivativessuch as 3,3-ioene, N-(cycloalkyl)alkylamines and poliglusam, insolublequaternized polystyrenes, saponins and mixtures thereof. Other usefulbile acid sequestrants are disclosed in PCT Patent Applications Nos. WO97/11345 and WO 98/57652, and U.S. Pat. Nos. 3,692,895 and 5,703,188which are incorporated herein by reference. Suitable inorganiccholesterol sequestrants include bismuth salicylate plus montmorilloniteclay, aluminum hydroxide and calcium carbonate antacids.

Also useful with the present invention are methods of treatment that canfurther comprise administering at least one (one or more) activators forperoxisome proliferator-activated receptors (PPAR). These activators actas agonists for the peroxisome proliferator-activated receptors. Threesubtypes of PPAR have been identified, and these are designated asperoxisome proliferator-activated receptor alpha (PPARα), peroxisomeproliferator-activated receptor gamma (PPARγ) and peroxisomeproliferator-activated receptor delta (PPARδ). It should be noted thatPPARδ is also referred to in the literature as PPARβ and as NUC1, andeach of these names refers to the same receptor.

PPARα regulates the metabolism of lipids. PPARα is activated by fibratesand a number of medium and long-chain fatty acids, and it is involved instimulating β-oxidation of fatty acids. The PPARγ receptor subtypes areinvolved in activating the program of adipocyte differentiation and arenot involved in stimulating peroxisome proliferation in the liver. PPARδhas been identified as being useful in increasing high densitylipoprotein (HDL) levels in humans. See, e.g., WO 97/28149.

PPARα activator compounds are useful for, among other things, loweringtriglycerides, moderately lowering LDL levels and increasing HDL levels.Useful examples of PPARα activators include the fibrates discussedabove.

Other examples of PPARα activators useful with the practice of thepresent invention include suitable fluorophenyl compounds as disclosedin U.S. Pat. No. 6,028,109 which is incorporated herein by reference;certain substituted phenylpropionic compounds as disclosed in WO00/75103 which is incorporated herein by reference; and PPARα activatorcompounds as disclosed in WO 98/43081 which is incorporated herein byreference.

Non-limiting examples of PPARγ activator include suitable derivatives ofglitazones or thiazolidinediones, such as, troglitazone (such asREZULIN® troglitazone(-5-[[4-[3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione)commercially available from Parke-Davis); rosiglitazone (such asAVANDIA® rosiglitazone maleate(-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione,(Z)-2-butenedioate) (1:1) commercially available from SmithKlineBeecham) and pioglitazone (such as ACTOS™ pioglitazone hydrochloride(5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-]thiazolidinedionemonohydrochloride) commercially available from Takeda Pharmaceuticals).Other useful thiazolidinediones include ciglitazone, englitazone,darglitazone and BRL 49653 as disclosed in WO 98/05331 which isincorporated herein by reference; PPARγ activator compounds disclosed inWO 00/76488 which is incorporated herein by reference; and PPARyactivator compounds disclosed in U.S. Pat. No. 5,994,554 which isincorporated herein by reference.

Other useful classes of PPARγ activator compounds include certainacetylphenols as disclosed in U.S. Pat. No. 5,859,051 which isincorporated herein by reference; certain quinoline phenyl compounds asdisclosed in WO 99/20275 which is incorporated herein by reference; arylcompounds as disclosed by WO 99/38845 which is incorporated herein byreference; certain 1,4-disubstituted phenyl compounds as disclosed in WO00/63161; certain aryl compounds as disclosed in WO 01/00579 which isincorporated herein by reference; benzoic acid compounds as disclosed inWO 01/12612 & WO 01/12187 which are incorporated herein by reference;and substituted 4-hydroxy-phenylalconic acid compounds as disclosed inWO 97/31907 which is incorporated herein by reference.

PPARδ compounds are useful for, among other things, loweringtriglyceride levels or raising HDL levels. Non-limiting examples ofPPARδ activators include suitable thiazole and oxazole derivates, suchas C.A.S. Registry No. 317318-32-4, as disclosed in WO 01/00603 which isincorporated herein by reference); certain fluoro, chloro or thiophenoxy phenylacetic acids as disclosed in WO 97/28149 which isincorporated herein by reference; suitable non-β-oxidizable fatty acidanalogues as disclosed in U.S. Pat. No. 5,093,365 which is incorporatedherein by reference; and PPARδ compounds as disclosed in WO 99/04815which is incorporated herein by reference.

Moreover, compounds that have multiple functionality for activatingvarious combinations of PPARα, PPARγ and PPARδ are also useful with thepractice of the present invention. Non-limiting examples include certainsubstituted aryl compounds as disclosed in U.S. Pat. No. 6,248,781; WO00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; and WO00/63153, all of which are incorporated herein by reference, aredescribed as being useful PPARα and/or PPARγ activator compounds. Othernon-limiting examples of useful PPARα and/or PPARγ activator compoundsinclude activator compounds as disclosed in WO 97/25042 which isincorporated herein by reference; activator compounds as disclosed in WO00/63190 which is incorporated herein by reference; activator compoundsas disclosed in WO 01/21181 which is incorporated herein by reference;biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120 which isincorporated herein by reference; compounds as disclosed in WO 00/63196and WO 00/63209 which are incorporated herein by reference; substituted5-aryl-2,4-thiazolidinediones compounds as disclosed in U.S. Pat. No.6,008,237 which is incorporated herein by reference;arylthiazolidinedione and aryloxazolidinedione compounds as disclosed inWO 00/78312 and WO 00/78313G which are incorporated herein by reference;GW2331 or(2-(4-[difluorophenyl]-1heptylureido)ethyl]phenoxy)-2-methylbutyriccompounds as disclosed in WO 98/05331 which is incorporated herein byreference; aryl compounds as disclosed in U.S. Pat. No. 6,166,049 whichis incorporated herein by reference; oxazole compounds as disclosed inWO 01/17994 which is incorporated herein by reference; and dithiolanecompounds as disclosed in WO 01/25225 and WO 01/25226 which areincorporated herein by reference.

Other useful PPAR activator compounds include substitutedbenzylthiazolidine-2,4-dione compounds as disclosed in WO 01/14349, WO01/14350 and WO/01/04351 which are incorporated herein by reference;mercaptocarboxylic compounds as disclosed in WO 00/50392 which isincorporated herein by reference; ascofuranone compounds as disclosed inWO 00/53563 which is incorporated herein by reference; carboxyliccompounds as disclosed in WO 99/46232 which is incorporated herein byreference; compounds as disclosed in WO 99/12534 which is incorporatedherein by reference; benzene compounds as disclosed in WO 99/15520 whichis incorporated herein by reference; o-anisamide compounds as disclosedin WO 01/21578 which is incorporated herein by reference; and PPARactivator compounds as disclosed in WO 01/40192 which is incorporatedherein by reference.

Also useful with the present invention are methods of treatment whichfurther comprise administering hormone replacement agents andcompositions. Useful hormone agents and compositions for hormonereplacement therapy of the present invention include androgens,estrogens, progestins, their pharmaceutically acceptable salts andderivatives. Combinations of these agents and compositions are alsouseful.

The cathepsin inhibitors of the present invention are useful in thetreatment of central nervous system diseases such as depression,cognitive function diseases and neurodegenerative diseases such asParkinson's disease, senile dementia as in Alzheimer's disease, andpsychoses of organic origin. In particular, the cathepsin inhibitors ofthe present invention can improve motor-impairment due toneurodegenerative diseases such as Parkinson's disease.

The other agents known to be useful in the treatment of Parkinson'sdisease which can be administered in combination with the cathepsininhibitors of the present invention include: L-DOPA; dopaminergicagonists such as quinpirole, ropinirole, pramipexole, pergolide andbromocriptine; MAO-B inhibitors such as deprenyl and selegiline; DOPAdecarboxylase inhibitors such as carbidopa and benserazide; and COMTinhibitors such as tolcapone and entacapone.

A preferred dosage for the administration of a compound of the presentinvention is about 0.001 to 500 mg/kg of body weight/day of a compoundof the present invention or a pharmaceutically acceptable salt or esterthereof. An especially preferred dosage is about 0.01 to 25 mg/kg ofbody weight/day of a compound of the present invention or apharmaceutically acceptable salt or ester thereof.

The phrases “effective amount” and “therapeutically effective amount”mean that amount of a compound of the present invention, and otherpharmacological or therapeutic agents described herein, that will elicita biological or medical response of a tissue, a system, or a subject(e.g., animal or human) that is being sought by the administrator (suchas a researcher, doctor or veterinarian) which includes alleviation ofthe symptoms of the condition or disease being treated and theprevention, slowing or halting of progression of one or more of thepresently claimed diseases. The formulations or compositions,combinations and treatments of the present invention can be administeredby any suitable means which produce contact of these compounds with thesite of action in the body of, for example, a mammal or human.

For administration of pharmaceutically acceptable salts of the abovecompounds, the weights indicated above refer to the weight of the acidequivalent or the base equivalent of the therapeutic compound derivedfrom the salt.

As described above, this invention includes combinations comprising anamount of at least one compound of the presently claimed methods or apharmaceutically acceptable salt or ester thereof, and an amount of oneor more additional therapeutic agents listed above (administeredtogether or sequentially) wherein the amounts of thecompounds/treatments result in desired therapeutic effect.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts). Thus, for illustration purposes, a compound of thepresent invention and an additional therapeutic agent may be present infixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule,a tablet and the like).

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange. Compounds of the present invention may also be administeredsequentially with known therapeutic agents when a combinationformulation is inappropriate. The invention is not limited in thesequence of administration; compounds of the present invention may beadministered either prior to or after administration of the knowntherapeutic agent. Such techniques are within the skills of personsskilled in the art as well as attending physicians.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays for measuring HCV viralactivity or cathepsin activity, such as are well known to those skilledin the art.

Preferably, in the practice of the invention, the concentration ofHCV-RNA is quantitatively measured by research-based reversetranscriptase polymerase chain reaction (RT-PCR) assay well known to theskilled clinician. Specifically, the Hepatitis C virus (HCV) RNA ismeasured by extracting total RNA from plasma or serum samples and usingan in-house real-time reverse transcriptase polymerase chain reaction(RT-PCR) assay. The amplification target is the 5′-Untranslated region(UTR) of the HCV genome. An internal RNA control is added to each sampleto assess the efficiency of RNA extraction. Appropriate negative andpositive controls are added in each assay run. The assay method has beenvalidated against the WHO International Standard for HCV. HCV RNA amountin a sample is reported as copies of HCV RNA per mL of sample and alsoas HCV IU per mL of sample. Results for sample at or above 100 copies ofHCV RNA per mL are denoted as POS. On the other hand, ND stands for <100copies of HCV RNA or <29 IU of HCV per mL of sample. The RT-PCR assayhas a lower limit of detection of HCV-RNA viral load of 29 InternationalUnits (IU) per milliliter (ml) of plasma of a subject. The concentrationof 29 IU/ml HCV-RNA is equal to a concentration of 100 copies of HCV RNAper milliliter of plasma. With respect to quantifying HCV RNA with thert-PCR methodology referred to herein, one (1) copy of HCV RNA equals0.29 IU, such that 100 copies of HCV RNA per milliliter of plasma is 29International Units per milliliter of plasma. Serum HCV-RNA/qPCR testingand HCV genotype testing will be performed by a central laboratory. Seealso J. G. McHutchinson et al. (N. Engl. J. Med., 1998, 339:1485-1492),and G. L. Davis et al. (N. Engl. J. Med. 339:1493-1499). HCV genotype isdetermined by sequencing the PCR amplified DNA fragment of the 5′-UTR ofthe HCV genome. The sequence is then aligned with the publishedsequences of the HCV genotypes to arrive at a determination.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition. Thecompositions of the present invention comprise at least one activeingredient, as defined above, together with one or more acceptablecarriers, adjuvants or vehicles thereof and optionally other therapeuticagents. Each carrier, adjuvant or vehicle must be acceptable in thesense of being compatible with the other ingredients of the compositionand not injurious to the mammal in need of treatment.

Accordingly, this invention also relates to pharmaceutical compositionscomprising at least one compound utilized in the presently claimedmethods, or a pharmaceutically acceptable salt or ester thereof and atleast one pharmaceutically acceptable carrier, adjuvant or vehicle.

In yet another embodiment, the present invention discloses methods forpreparing pharmaceutical compositions comprising the inventive compoundsas an active ingredient. In the pharmaceutical compositions and methodsof the present invention, the active ingredients will typically beadministered in admixture with suitable carrier materials suitablyselected with respect to the intended form of administration, i.e. oraltablets, capsules (either solid-filled, semi-solid filled or liquidfilled), powders for constitution, oral gels, elixirs, dispersiblegranules, syrups, suspensions, and the like, and consistent withconventional pharmaceutical practices. For example, for oraladministration in the form of tablets or capsules, the active drugcomponent may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier, such as lactose, starch, sucrose, cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, talc,mannitol, ethyl alcohol (liquid forms) and the like. Moreover, whendesired or needed, suitable binders, lubricants, disintegrating agentsand coloring agents may also be incorporated in the mixture. Powders andtablets may be comprised of from about 5 to about 95 percent inventivecomposition.

In one embodiment, the adjuvant is at least one pharmaceuticallyacceptable surfactant or at least one pharmaceutically acceptableacidifying agent or both. When desired or needed, suitable carriers andother excipients (such as binders, glidents, lubricants, anddisintegrants) may also be incorporated in the formulation. Surfactantsmay be present in the pharmaceutical formulations of the presentinvention in an amount of about 0.1 to about 10% by weight or about 1 toabout 5% by weight. Acidifying agents may be present in thepharmaceutical formulations of the present invention in a total amountof about 0.1 to about 10% by weight or about 1 to 5% by weight.

Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes. Among thelubricants there may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrants include starch, methylcellulose, guar gum and the like.

Sweetening and flavoring agents and preservatives may also be includedwhere appropriate. Some of the terms noted above, namely disintegrants,diluents, lubricants, binders and the like, are discussed in more detailbelow.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. HCV inhibitory activity and thelike. Suitable dosage forms for sustained release include layeredtablets containing layers of varying disintegration rates or controlledrelease polymeric matrices impregnated with the active components andshaped in tablet form or capsules containing such impregnated orencapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injections or addition of sweeteners and pacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions may take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally, intravenously orsubcutaneously.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active components, e.g., aneffective amount to achieve the desired purpose.

Some useful terms are described below:

Capsule—refers to a special container or enclosure made of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch forholding or containing compositions comprising the active ingredients.Hard shell capsules are typically made of blends of relatively high gelstrength bone and pork skin gelatins. The capsule itself may containsmall amounts of dyes, opaquing agents, plasticizers and preservatives.

Tablet—refers to a compressed or molded solid dosage form containing theactive ingredients with suitable diluents. The tablet can be prepared bycompression of mixtures or granulations obtained by wet granulation, drygranulation or by compaction.

Oral gel—refers to the active ingredients dispersed or solubilized in ahydrophilic semi-solid matrix.

Powder for constitution refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

Diluent—refers to substances that usually make up the major portion ofthe composition or dosage form. Suitable diluents include sugars such aslactose, sucrose, mannitol and sorbitol; starches derived from wheat,corn, rice and potato; and celluloses such as microcrystallinecellulose. The amount of diluent in the composition can range from about10 to about 90% by weight of the total composition, preferably fromabout 25 to about 75%, more preferably from about 30 to about 60% byweight, even more preferably from about 12 to about 60%.

Disintegrant—refers to materials added to the composition to help itbreak apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches; “cold water soluble” modified starchessuch as sodium carboxymethyl starch; natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar; cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose;microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose; alginates such as alginic acid and sodiumalginate; clays such as bentonites; and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 15% by weight of the composition, more preferably from about 4 toabout 10% by weight.

Binder—refers to substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose; starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 2 to about 20% by weight of the composition, morepreferably from about 3 to about 10% by weight, even more preferablyfrom about 3 to about 6% by weight.

Lubricant—refers to a substance added to the dosage form to enable thetablet, granules, etc. after it has been compressed, to release from themold or die by reducing friction or wear. Suitable lubricants includemetallic stearates such as magnesium stearate, calcium stearate orpotassium stearate; stearic acid; high melting point waxes; and watersoluble lubricants such as sodium chloride, sodium benzoate, sodiumacetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricantsare usually added at the very last step before compression, since theymust be present on the surfaces of the granules and in between them andthe parts of the tablet press. The amount of lubricant in thecomposition can range from about 0.2 to about 5% by weight of thecomposition, preferably from about 0.5 to about 2%, more preferably fromabout 0.3 to about 1.5% by weight.

Glident—material that prevents caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

Coloring agents—excipients that provide coloration to the composition orthe dosage form. Such excipients can include food grade dyes and foodgrade dyes adsorbed onto a suitable adsorbent such as clay or aluminumoxide. The amount of the coloring agent can vary from about 0.1 to about5% by weight of the composition, preferably from about 0.1 to about 1%.

Bioavailability—refers to the rate and extent to which the active drugingredient or therapeutic moiety is absorbed into the systemiccirculation from an administered dosage form as compared to a standardor control.

Conventional methods for preparing tablets are known. Such methodsinclude dry methods such as direct compression and compression ofgranulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

The term pharmaceutical composition is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the aforesaid “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating asubject by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects. Suitable dosage forms for sustainedrelease include layered tablets containing layers of varyingdisintegration rates or controlled release polymeric matricesimpregnated with the active components and shaped in tablet form orcapsules containing such impregnated or encapsulated porous polymericmatrices.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of thepresent invention and/or the pharmaceutically acceptable salts or estersthereof will be regulated according to the judgment of the attendingclinician considering such factors as age, condition and size of thepatient as well as severity of the symptoms being treated. A typicalrecommended daily dosage regimen for oral administration can range fromabout 50 mg/day to about 3,000 mg/day, preferably from about 50 mg/dayto about 2,400 mg/day, more preferably from about 50 mg/day to about1,200 mg/day, in two to four divided doses.

The pharmaceutical formulation in a unit dosage form may contain about50 mg to about 1000 mg of the compound of Formulae I-XXVI. Other unitdosage forms may contain from about 50 mg to about 800 mg, or from about50 mg to about 600 mg, or from about 50 mg to about 400 mg, or fromabout 50 mg to about 200 mg according to the particular application. Inone embodiment, the unit dosage form is tablet containing about 400 mgof the active compound.

EXAMPLE

A single dose, randomized, two-treatment (fed vs. fasted) study wasconducted to assess the effect of food on bioavailability of a compoundof the present invention (SCH 503034 or Compound Ia). A single oral doseof 600 mg. of compound of Formula Ia was administered to two groups ofhealthy subjects. Group A received the dose after an overnight 10-hourfast; Group B received the dose about twenty minutes after consuming ahigh fat breakfast of 850 calories having 53.8 g fat (57% of caloriesfrom fat) or low fat breakfast of 451 calories. Blood samples werecollected immediately prior to dosing (time zero) and at times 0.5, 1,1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours post dose. Resultsof measurement of mean maximum concentration (C_(max)) of compound ofFormula Ia in serum in ng/ml are shown in Table 1 and FIG. 1 (graph ofmean plasma concentration of the compound versus Time). Calculations ofAUC(tf) (area under the curve at time final), AUC(I) (area under thecurve extrapolated to infinity), t½ (time at which one-half of thecompound has disappeared from the blood), Tmax (time at which maximumserum concentration is achieved), CL/F (clearance divided bybioavailability), and Vd/F (volume of distribution divided bybioavailability) are made according to standard formulas known to oneskilled in the art of drug metabolism and pharmacokintics. TABLE 1 Mean(CV %) Pharmacokinetic Parameters of SCH 503034 Under Fasted and Fed(with High Fat and Non Fat Diet) Conditions (Balanced Data) Fed FedFasted (High Fat Diet) (Non Fat Diet) Param- CV CV CV eter^(a) n Mean(%) n Mean (%) n Mean (%) Cmax 11 502 38 11 1148 48 11 639 38 AUC(tf) 111557 28 11 5090 43 11 3036 11 AUC(l) 8 1627 29 8 4435 29 8 2749 8 t½ 87.61 72 8 2.01 47 8 3.2 8 CL/F 8 407 38 8 144.0 24 8 243 8 Vd/F 8 457776 8 418.5 54 8 1140 8 Tmax^(c) 11 1.5 (1-2) 11 4 (2-12) 11 4 (2.5-11)^(a)(unit): AUC-ng · hr/mL; Cmax-ng/mL; Tmax, t½-hr; CL/F-L/hr; Vd/F-L.^(c)Median (range).

As shown in FIG. 1, peak serum levels (C_(max)) in subjects dosed withfood were delayed as compared to peak serum levels in fasting subjects.Additionally, a higher peak serum level was obtained in subjects dosedwith food as compared with fasting subjects, indicating that dosing withfood increases bioavailability of the compound of Formula Ia andincreases serum levels of the compound of Formula Ia. The mean Cmaxvalues were 502, 1148 and 639 ng/mL (balanced data) under fasted stateand fed state with high fat and non fat diets, respectively, and wereachieved at 1.5, 12 and 11 hours (median Tmax value), respectively. TheSCH 503034 was absorbed more slowly in the fed state. In 8 of the 12subjects who completed all three periods, there appeared to be anabsorption lag time of 0.5 hour in the fed state with high fat diet and7 subjects with non fat diet also had 0.5 hour absorption lag time.

The relative bioavailability of SCH 503034 under fed and fastedconditions are presented below: Relative Bioavailability of SCH 503034under Fed and fasted States: Balanced Data Ratio Estimate 90% ConfidenceParameters^(a) Compare (%)^(c) Interval Cmax — — — B/A 223 169-293 C/A129 98-170 AUC (tf) — — — B/A 317 266-377 C/A 182 153-217 AUC(l) — — —B/A 276 238-319 C/A 167 145-194^(a)(unit): AUC-ng · hr/mL; Cmax-ng/mL; Tmax, t½-hr; CL/F-L/hr; Vd/F-L.^(c)Median (range).Based on ratio estimates, the mean AUCs were increased by over 200% forhigh fat diet and about 100% for non fat diet, respectively, relative tofasted state. The corresponding values for Cmax were increased by 123and 29%, respectively.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications that are within the spirit and scopeof the invention, as defined by the appended claims.

Each document (including granted patents, published patent applications,and nonpatent publications such as journal articles) referred to in thisapplication is incorporated in its entirety by reference for allpurposes.

The Following Experimental Section Applies for the Preparation of theCompounds of Formula XI:

Abbreviations which are used in the descriptions of the schemes,preparations and the examples that follow are:

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

EtOAc: Ethyl acetate

AcOH: Acetic acid

HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one

EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

NMM: N-Methylmorpholine

ADDP: 1,1′-(Azodicarbobyl)dipiperidine

DEAD: Diethylazod icarboxylate

MeOH: Methanol

EtOH: Ethanol

Et₂O: Diethyl ether

DMSO: Dimethylsulfoxide

HOBt: N-Hydroxybenzotriazole

PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate

DCM: Dichloromethane

DCC: 1,3-Dicyclohexylcarbodiimide

TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy

Phg: Phenylglycine

Chg: Cyclohexylglycine

Bn: Benzyl

Bzl: Benzyl

Et: Ethyl

Ph: Phenyl

iBoc: isobutoxycarbonyl

iPr: isopropyl

^(t)Bu or Bu^(t): tert-Butyl

Boc: tert-Butyloxycarbonyl

Cbz: Benzyloxycarbonyl

Cp: Cylcopentyldienyl

Ts: p-toluenesulfonyl

MCPBA: 3-chloroperbenzoic acid.

Me: Methyl

HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

DMAP: 4-N,N-Dimethylaminopyridine

Bop: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate

PCC: Pyridiniumchlorochromate

Other abbreviations are commonly used abbreviations Such as according tothe guidelines published by Journal of Organic Chemistry.

General Schemes for Preparation of Target Compounds

Compounds of the present invention were synthesized using the generalschemes (Methods A-E) described below.

Method A

Deprotection of the N-Boc functionality of 1.01 under acidic conditionsprovided the hydrochloride salt 1.02 which was subsequently coupled withN-Boc-tert-leucine under peptide coupling methodology (Louis A Carpinoet al. “Preparation of uronium and immonium salts for peptide coupling”,WO 2002094822, pp. 76) to afford 1.03. N-Boc deprotection followed bytreatment with appropriate isocyanate gave the urea 1.05. Hydrolysis ofthe methyl ester provided the acid 1.06. Peptide coupling of the acid1.06 with the appropriate P₁-P′ primary amide moiety afforded thehydroxyl amide 1.07. Oxidation (Moffatt, or Dess-Martin's) resulted inthe target compound 1.08.

Method BPeptide coupling of the acid 1.06 with the appropriate P₁-P′ secondaryamide moiety afforded the hydroxylamide 1.09. Oxidation (Moffatt orDess-Martin's) resulted in the target compound 1.10.Method CIn another variation, peptide coupling of the N-Boc-P2-P₃-acid 1.03 withthe appropriate P₁-P′ amide moiety afforded the hydroxylamide 1.11.Oxidation (Moffatt or Dess-Martin's) resulted in the keto-amide 1.12.Deprotection of the N-Boc using either formic acid or 4 M HCl in dioxanegave the formate or hydrochloride salt 1.13. Treatment with a suitableisocyanate (or isocyanate equivalent) resulted in the target compound1.14.

Method DIn yet another variation, the hydrochloride salt 1.13 was converted tothe 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenylchloroformate. Subsequent treatment with an amine (or aminehydrochloride salt) of choice provided the target compound 1.14.

Method EIn yet another variation, the dipeptide hydrochloride salt 1.04 wasconverted to the 4-nitrophenyl carbamate as described above. Treatmentwith an amine (or amine hydrochloride salt) of choice provided the ureaderivative 1.05. Hydrolysis and further elaboration as described inMethods A/B provided the target compounds 1.14.

The Following Experimental Section Applies for the Preparation of theCompounds of Formula XII:Abbreviations which are used in the descriptions of the schemes,preparations and the examples that follow are:THF: TetrahydrofuranDMF: N,N-DimethylformamideEtOAc: Ethyl acetateAcOH: Acetic acidHOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-oneEDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideNMM: N-MethylmorpholineADDP: 1,1′-(Azodicarbobyl)dipiperidineDEAD: DiethylazodicarboxylateMeOH: MethanolEtOH: EthanolEt₂O: Diethyl etherDMSO: DimethylsulfoxideHOBt: N-HydroxybenzotriazolePyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphateDCM: DichloromethaneDCC: 1,3-DicyclohexylcarbodiimideTEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxyPhg: PhenylglycineChg: CyclohexylglycineBn: BenzylBzl: BenzylEt: EthylPh: PhenyliBoc: isobutoxycarbonyliPr: isopropyl^(t)Bu or Bu^(t): tert-ButylBoc: tert-ButyloxycarbonylCbz: BenzyloxycarbonylCp: CylcopentyldienylTs: p-toluenesulfonylMe: MethylHATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphateDMAP: 4-N,N-DimethylaminopyridineBOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphatePCC: Pyridiniumchlorochromate

General Schemes for Preparation of Target Compounds

Compounds of the present invention were synthesized using the generalschemes (Methods A-E) described below.

Method A:

Deprotection of the N-Boc functionality of 1.01 under acidic conditionsprovided the hydrochloride salt 1.02 which was subsequently coupled withN-Boc-tert-leucine under peptide coupling methodology to afford 1.03.N-Boc deprotection followed by treatment with appropriate isocyanategave the urea 1.05. Hydrolysis of the methyl ester provided the acid1.06. Peptide coupling of the acid 1.06 with the appropriate P₁-P′primary amide moiety afforded the hydroxylamide 1.07. Oxidation (Moffattor related process—T. T. Tidwell, Synthesis, 1990, 857; orDess-Martin's—J. Org. Chem., 1983, 48, 4155) resulted in the targetcompound 1.08.

Method BPeptide coupling of the acid 1.06 with the appropriate P₁-P′ secondaryamide moiety afforded the hydroxylamide 1.09. Oxidation (Moffatt orDess-Martin's) resulted in the target compound 1.10.

Method CIn another variation, peptide coupling of the N-Boc-P₂-P₃-acid 1.17 withthe appropriate P₁-P′ amide moiety afforded the hydroxylamide 1.11.Oxidation (Moffatt or Dess-Martin's) resulted in the keto amide 1.12.Deprotection of the N-Boc functionality gave the hydrochloride salt1.13. Treatment with a suitable isocyanate (or isocyanate equivalent)resulted in the target compound 1.14.

Method DIn yet another variation, the hydrochloride salt 1.13 was converted tothe 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenylchloroformate. Subsequent treatment with an amine (or aminehydrochloride salt) of choice provided the target compound 1.14.

Method EIn yet another variation, the dipeptide hydrochloride salt 1.03 wasconverted to the 4-nitrophenyl carbamate as described above. Treatmentwith an amine (or amine hydrochloride salt) of choice provided the ureaderivative 1.05. Hydrolysis and further elaboration as described inMethods A/B provided the target compounds 1.14.

The following experimental section applies for the preparation of thecompounds of Formula XIII:

Abbreviations which are used in the descriptions of the schemes,preparations and the examples that follow are:

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

EtOAc: Ethyl acetate

AcOH: Acetic acid

HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one

EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

NMM: N-Methylmorpholine

ADDP: 1,1′-(Azodicarbobyl)dipiperidine

DEAD: Diethylazodicarboxylate

DIAD: Diisopropylazodicarboxylate

MeOH: Methanol

EtOH: Ethanol

Et₂O: Diethyl ether

DMSO: Dimethylsulfoxide

HOBt: N-Hydroxybenzotriazole

PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate

DCM: Dichloromethane

DCC: 1,3-Dicyclohexylcarbodiimide

TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy

Phg: Phenylglycine

Chg: Cyclohexylglycine

Bn: Benzyl

Bz: Benzyl

Et: Ethyl

Ph: Phenyl

iBoc: isobutoxycarbonyl

iPr: isopropyl

^(t)Bu or Bu^(t): tert-Butyl

Boc: tert-Butyloxycarbonyl

Cbz: Benzyloxycarbonyl

Cp: Cylcopentyldienyl

Ts: p-toluenesulfonyl

Me: Methyl

Ms or Mesyl: Methane sulfonyl

HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

DMAP: 4-N,N-Dimethylaminopyridine

Bop: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate

PCC: Pyridiniumchlorochromate

DIBAL-H: diisopropyl aluminum hydride

rt or RT: Room temperature

quant.: Quantitative yield

h or hr: hour

min: minute

TFA: Trifluoroacetic acid

General Schemes for Preparation of Target Compounds

Compounds of the present invention were synthesized using the generalschemes (Methods A-E) described below.

Method A

Deprotection of the N-Boc functionality of 1.01 under acidic conditionsprovided the hydrochloride salt 1.02 which was subsequently coupled withN-Boc-tert-leucine under peptide coupling methodology to afford 1.03.N-Boc deprotection followed by treatment with appropriate isocyanategave the urea 1.05. Hydrolysis of the methyl ester provided the acid1.06. Peptide coupling of the acid 1.06 with the appropriate P₁-P′primary amide moiety afforded the hydroxylamide 1.07. Oxidation (Moffattor related process—T. T. Tidwell, Synthesis, 1990, 857; or Dess-Martin'speriodinane (J. Org. Chem., 1983, 48, 4155) resulted in the targetcompound 1.08.

Method BPeptide coupling of the acid 1.06 with the appropriate P₁-P′ secondaryamide moiety afforded the hydroxylamide 1.09. Oxidation (Moffatt orDess-Martin's) resulted in the target compound 1.10.

Method CIn another variation, peptide coupling of the N-Boc-P₂-P₃-acid 1.17 withthe appropriate P₁-P′ amide moiety afforded the hydroxylamide 1.11.Oxidation (Moffatt or Dess-Martin's) resulted in the keto amide 1.12.Deprotection of the N-Boc functionality gave the hydrochloride salt1.13. Treatment with a suitable isocyanate (or isocyanate equivalent)resulted in the target compound 1.14.

Method DIn yet another variation, the hydrochloride salt 1.13 was converted tothe 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenylchloroformate. Subsequent treatment with an amine (or aminehydrochloride salt) of choice provided the target compound 1.14.

Method EIn yet another variation, the dipeptide hydrochloride salt 1.03 wasconverted to the 4-nitrophenyl carbamate as described above. Treatmentwith an amine (or amine hydrochloride salt) of choice provided the ureaderivative 1.05. Hydrolysis and further elaboration as described inMethods A/B provided the target compounds 1.14.

The Following Experimental Section Applies for the Preparation of theCompounds of Formula XIV:

For the procedures described below, the following abbreviations areused:

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

EtOAc: Ethyl acetate

AcOH: Acetic acid

HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one

EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

NMM: N-Methylmorpholine

ADDP: 1,1′-(Azodicarbobyl)dipiperidine

DEAD: Diethylazodicarboxylate

MeOH: Methanol

EtOH: Ethanol

Et2O: Diethyl ether

DMSO: Dimethylsulfoxide

HOBt: N-Hydroxybenzotriazole

PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate

DCM: Dichloromethane

DCC: 1,3-Dicyclohexylcarbodiimide

TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy

Phg: Phenylglycine

Chg: Cyclohexylglycine

Bn: Benzyl

Bzl: Benzyl

Et: Ethyl

Ph: Phenyl

DMF-DMA: N,N-Dimethylformamide-dimethylacetal

iBoc: isobutoxycarbonyl

iPr: isopropyl

^(t)Bu or Bu^(t): tert-Butyl

Boc: tert-Butyloxycarbonyl

Cbz: Benzyloxycarbonyl

Cp: Cylcopentyldienyl

Ts: p-toluenesulfonyl

Me: Methyl

HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

DMAP: 4-N,N-Dimethylaminopyridine

BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate

PCC: Pyridiniumchlorochromate

KHMDS: Potassium Hexamethyldisilazide or Potassiumbis(trimethylsilylamide)

NaHMDS: Sodium Hexamethyldisilazide or Sodium bis(trimethylsilylamide)

LiHMDS: Lithium Hexamethyldisilazide or Lithium bis(trimethylsilylamide)

10% Pd/C: 10% Palladium on carbon (by weight).

TG: Thioglycerol

General Schemes for Preparation of Target Compounds

Compounds of the present invention were synthesized using the generalschemes (Methods A-E) described below.

Method A

Deprotection of the N-Boc functionality of 1.01 under acidic conditionsprovided the hydrochloride salt 1.02 which was subsequently coupled withN-Boc-tert-leucine under peptide coupling methodology to afford 1.03.N-Boc deprotection followed by treatment with appropriate isocyanategave the urea 1.05. Hydrolysis of the methyl ester provided the acid1.06. Peptide coupling of the acid 1.06 with the appropriate P₁-P′primary amide moiety afforded the hydroxylamide 1.07. Oxidation (Moffattoxidation or related process—see, T. T. Tidwell, Synthesis, 1990, 857),or Dess-Martin Periodinane—J. Org. Chem., (1983) 48, 4155) resulted inthe target compound 1.08.

Method B

Peptide coupling of the acid 1.06 with the appropriate P₁-P′ secondaryamide moiety afforded the hydroxylamide 1.09. Oxidation (Moffatt orDess-Martin's) resulted in the target compound 1.10.

Method C

In another variation, peptide coupling of the N-Boc-P2-P₃-acid 1.17 withthe appropriate P₁-P′ amide moiety afforded the hydroxylamide 1.11.Oxidation (Moffatt or Dess-Martin Periodinane) resulted in the ketoamide 1.12. Deprotection of the N-Boc functionality gave thehydrochloride salt 1.13. Treatment with a suitable isocyanate (orisocyanate equivalent) resulted in the target compound 1.14.

Method D

In yet another variation, the hydrochloride salt 1.13 was converted tothe 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenylchloroformate. Subsequent treatment with an amine (or aminehydrochloride salt) of choice provided the target compound 1.14.

Method E

In yet another variation, the dipeptide hydrochloride salt 1.03 wasconverted to the 4-nitrophenyl carbamate as described above. Treatmentwith an amine (or amine hydrochloride salt) of choice provided the ureaderivative 1.05. Hydrolysis and further elaboration as described inMethods A/B provided the target compounds 1.14.

The Following Experimental Section Applies for the Preparation of theCompounds of Formula XV:

For the procedures described below, the following abbreviations areused:

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

EtOAc: Ethyl acetate

AcOH: Acetic acid

HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one

EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

NMM: N-Methylmorpholine

ADDP: 1,1′-(Azodicarbobyl)dipiperidine

DEAD: Diethylazodicarboxylate

MeOH: Methanol

EtOH: Ethanol

Et2O: Diethyl ether

DMSO: Dimethylsulfoxide

HOBt: N-Hydroxybenzotriazole

PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate

DCM: Dichloromethane

DCC: 1,3-Dicyclohexylcarbodiimide

TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy

Phg: Phenylglycine

Chg: Cyclohexylglycine

Bn: Benzyl

Bzl: Benzyl

Et: Ethyl

Ph: Phenyl

iBoc: isobutoxycarbonyl

iPr: isopropyl

^(t)Bu or Bu^(t): tert-Butyl

Boc: tert-Butyloxycarbonyl

Cbz: Benzyloxycarbonyl

Cp: Cylcopentyldienyl

Ts: p-toluenesulfonyl

Me: Methyl

HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

DMAP: 4-N,N-Dimethylaminopyridine

BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate

PCC: Pyridiniumchlorochromate

KHMDS: Potassium Hexamethyldisilazide or Potassiumbis(trimethylsilylamide)

NaHMDS: Sodium Hexamethyldisilazide or Sodium bis(trimethylsilylamide)

LiHMDS: Lithium Hexamethyldisilazide or Lithium bis(trimethylsilylamide)

10% Pd/C: 10% Palladium on carbon (by weight).

Preparative Example 1

A solution of pyrazinecarboxylic acid 1a (3 g) in 150 mL of drydichloromethane and 150 mL of dry DMF was stirred at 0° C. and treatedwith HATU (1.4 eq, 6.03 g). L-cyclohexylglycine hydrochloride 1b (1.2eq, 6.03 g) was added in small portions. Then, N-methylmorpholine (4 eq,10 mL, d 0.920) was added dropwise. The reaction mixture was graduallywarmed to room temperature and stirred for 20 h. All the volatiles wereremoved under vacuum and the residue was dissolved in 500 mL of ethylacetate. The organic layer was washed with water (100 mL), aqueous 1NHCl (100 mL), aqueous saturated sodium bicarbonate solution (100 mL),and brine (100 mL). The organic layer was dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue waschromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7)to afford the product 1c as a white solid.

A solution of methyl ester 1c (6.5 g) in 270 mL of a 1:1:1 mixture ofTHF/MeOH/water was cooled to 0° C. and treated with lithium hydroxidemonohydrate (2.5 eq, 2.45 g). The mixture was stirred and monitored byTLC (acetone/hexanes; 2:8). When all the starting material had beenconsumed, the reaction mixture was treated with 100 mL of aqueous 1N HCland the mixture was concentrated on the rotavap. Dichloromethane (250mL) was added and layers separated. The aqueous layer was extracted withdichloromethane (3×80 mL). The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated to afford the product 1das a white solid.

The amino ester 1e was prepared following the method of R. Zhang and J.S. Madalengoitia (J. Org. Chem. 1999, 64, 330), with the exception thatthe Boc group was cleaved by the reaction of the Boc-protected aminoacid with methanolic HCl (4M HCl in dioxane was also employed for thedeprotection).(Note: In a variation of the reported synthesis, the sulfonium ylide wasreplaced with the corresponding phosphonium ylide).

A solution of Boc-tert-Leu 1f (Fluka, 5.0 g, 21.6 mmol) in dryCH₂Cl₂/DMF (50 mL, 1:1) was cooled to 0° C. and treated with the aminehydrochloride 1e (5.3 g, 25.7 mmol), NMM (6.5 g, 64.8 mmol) and BOPreagent (11.6 g, 25.7 mmol). The reaction was stirred at rt. for 24 h,diluted with aqueous HCl (1 M) and extracted with CH₂Cl₂. The combinedorganic layers were washed with aqueous 1M HCl, saturated NaHCO₃, brine,dried (MgSO₄), filtered and concentrated in vacuo and purified bychromatography (SiO₂, Acetone/Hexane 1:5) to yield 1g as a colorlesssolid.Step E

A solution of methyl ester 1g (4.0 g, 10.46 mmol) was dissolved in 4MHCl in dioxane and stirred at rt. for 3 h. The reaction mixture wasconcentrated in vacuo to obtain the amine hydrochloride salt, 1 h whichwas used without purification.

A solution of acid 1d (100 mg) in 5 mL of dry dichloromethane and 5 mLof dry DMF was stirred at 0° C. and treated with HATU (1.4 eq, 202 mg).The amine hydrochloride 1h (1.2 eq, 146 mg) was added. Then,N-methylmorpholine (4 eq, 0.17 mL, d 0.920) was also added. The reactionmixture was stirred at 0° C. overnight. All the volatiles were removedunder vacuum and the residue was dissolved in 80 mL of ethyl acetate.The organic layer was washed with water (10 mL), aqueous 1N HCl (10 mL),aqueous saturated sodium bicarbonate solution (10 mL), and brine (10mL). The organic layer was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed onsilica gel (gradient: acetone/hexanes; 1:9 to 4:6) to afford the product1i as a white solid.

A solution of methyl ester 1i (180 mg) in 9 mL of a 1:1:1 mixture ofTHF/MeOH/water was cooled to 0° C. and treated with lithium hydroxidemonohydrate (2.5 eq, 35 mg). The mixture was stirred and monitored byTLC (acetone/hexanes; 3:7). When all the starting material had beenconsumed, the reaction mixture was treated with 50 mL of aqueous 1N HCland the mixture was concentrated on the rotavap. Dichloromethane (80 mL)was added and layers separated. The aqueous layer was extracted withdichloromethane (3×50 mL). The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated to afford the product 1jas a white solid.

A solution of acid 1k (2 g) in 100 mL of dry dichloromethane and 5 mL ofDMF was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq,986 mg), BOP reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq,3.3 mL, d 0.920) in that order. The mixture was heated to 50° C.overnight. The reaction mixture was concentrated to half its volume anddiluted with 400 mL of ethyl acetate. The organic layer was washed withwater (80 mL), aqueous 1M HCl (80 mL), aqueous saturated sodiumbicarbonate solution (80 mL), and brine (80 mL). The organic layer wasdried over magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was chromatographed on silica gel (gradient:acetone/hexanes; 5:95 to 3:7) to afford the product 1l as a clear oil.

A solution of amide 1l (2.2 g) in 100 mL of dry THF was cooled to ° C.Lithium aluminum hydride solution (1.3 eq) was added dropwise. Thecooling bath was removed after 5 min and the mixture was allowed toreach room temperature. TLC analysis (ethyl acetate/hexanes; 2:8) showedthat all the starting material had been consumed. The excess LAH wascarefully quenched by addition of drops of aqueous saturated sodiumhydrogen sulfate. The mixture was diluted with 200 mL of ether andaqueous saturated sodium hydrogen sulfate was added in small portionsuntil a white solid precipitated. The mixture was filtered thru celiteand the filtrate was washed with 50 mL of brine. The organic layer wasdried over magnesium sulfate, filtered and concentrated. The residue waschromatographed on silica gel (gradient: ethyl acetate/hexanes; 5:95 to4:6) to afford the aldehyde product 1m as a colorless oil.

A solution of aldehyde 1m (1.8 g) in 100 mL of dry dichloromethane wastreated with isonitrile (1.1 eq, 680 mg) and acetic acid (2 eq, 1.02 mL,d 1.0149). The mixture was stirred overnight. All the volatiles wereremoved under vacuum and the residue was chromatographed on silica gel(gradient: ethyl acetate/hexanes; 2:8 to 6:4) to afford the product 1nas a white solid.

A solution of acetate 1n (1.6 g) in 60 mL of a 1:1:1 mixture ofTHF/MeOH/water was treated with lithium hydroxide monohydrate andstirred for approximately 1 h until all the starting material had beenconsumed as determined by TLC analysis (ethyl acetate/hexanes; 1:1). Thevolatiles were removed in rotavap and the residue was diluted withdichloromethane (150 mL). The layers were separated and the aqueouslayer was diluted with 30 mL of aqueous saturated sodium bicarbonatesolution and extracted with dichloromethane (3×80 mL). The combinedorganic layers were dried over magnesium sulfate, filtered andconcentrated to afford the product 1p as a white solid.

The N-Boc protected amine 1p (1.5 g) was dissolved in 20 mL of 4M HCl indioxane. The reaction mixture was stirred for about 1 h until all thestarting material had been consumed. All the volatiles were removedunder vacuum to afford the product 1q as a white solid.

A solution of acid 1j (50 mg) in 2 mL of dry dichloromethane and 2 mL ofdry DMF was stirred at 0° C. and treated with HATU (1.4 eq, 52 mg). Theamine hydrochloride 1q (1.2 eq, 26 mg) was added. Then,N-methylmorpholine (4 eq, 0.042 mL, d 0.920) was also added. Thereaction mixture was stirred at 0° C. overnight. All the volatiles wereremoved under vacuum and the residue was dissolved in 80 mL of ethylacetate. The organic layer was washed with water (10 mL), aqueous 1N HCl(10 mL), aqueous saturated sodium bicarbonate solution (10 mL), andbrine (10 mL). The organic layer was dried over magnesium sulfate,filtered and concentrated under reduced pressure. The product 1r wasused without further purification.

A solution of alcohol 1r (65 mg) in 5 mL of dry dichloromethane wastreated with Dess-Martin periodinane (3 eq, 121 mg). Reaction mixturewas stirred at room temperature for 45 min. The mixture was treated withaqueous 1M sodium thiosulfate solution (10 mL) and aqueous saturatedsodium bicarbonate solution (10 mL) and stirred for 15 min. The mixturewas extracted with dichloromethane (3×20 mL). The combined organiclayers were dried over magnesium sulfate, filtered, and concentrated.The residue was chromatographed on silica gel (gradient:acetone/hexanes; 2:8 to 5:5) to afford the product 1 as a white solid.

One skilled in the art would understand that other suitable compounds ofFormula XV can be prepared in a similar manner to that disclosed above.

The Following Experimental Section Applies for the Preparation of theCompounds of Formula XVI:

Preparative Example A

A solution of acid 1 (255 mg) in 5 mL of dry dichloromethane and 5 mL ofdry DMF was stirred at 0° C. and treated with HATU (368 mg). The aminehydrochloride 2 (201 mg) was added followed by addition ofN-methylmorpholine (0.42 mL). The reaction mixture was gradually warmedto room temperature and stirred overnight. All the volatiles wereremoved under vacuum and the residue was taken into 100 mL of ethylacetate. The organic layer was washed with aqueous 1N HCl (15 mL),aqueous saturated NaHCO3 (15 mL), water (15 mL), brine (15 mL), driedover MgSO4, filtered, and concentrated under reduced pressure to affordthe desired product A1. No further purification was carried out for theproduct.

A solution of A1 (360 mg) in 20 mL of a 1:1 mixture of toluene/DMSO wastreated with EDCI (1.3 g) and dichloroacetic acid (0.42 mL, d 1.563).Reaction mixture was stirred at room temperature for about 3 h. Thereaction mixture was diluted with dichloromethane (100 mL) and washedwith aqueous saturated NaHCO₃ (15 mL), aqueous 1N HCl (15 mL), and brine(15 mL). The organic layer was dried over magnesium sulfate, filtrated,and concentrated under reduced pressure. The residue was chromatographedon silica gel (gradient: acetone/hexanes; 2:8 to 5:5) to afford theproduct A2 in 84% yield.

The N-Boc protected amine A2 was treated with 10 mL of formic acid. Theresulting solution was stirred for 2 h. All the volatiles were removedunder reduced pressure. No further purification was done for the productA3.

To a solution of the amine salt A3 in 1 mL of dry methylene chloride wasadded N-methylmorpholine (0.037 mL, d 0.920). The resulting solution wascooled in an ice-water bath and a solution of isocyanate in toluene (2.5mL of a 0.135M soln) was slowly added. The mixture was stirred for 2 h(temp 0 to 25° C.). The reaction mixture was diluted with 60 mL ofdichloromethane and washed with 15 mL of aqueous 1N HCl. Aqueous layerwas back extracted with dichloromethane (2×20 mL). Combined organiclayers were dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was chromatographed on Silica gel(gradient: acetone/hexanes; 1:9 to 6:4) to give the product A (15 mg) asa white solid in 20% yield. HRMS (FAB) calcd for C₃₇H₅₃N₆O₇ [M+H]693.3976; found 693.3987.

One skilled in the art would understand that other suitable compounds ofFormula XVI can be prepared in a similar manner to that disclosed above.

The Following Experimental Section Applies for the Preparation of theCompounds of Formula XVII:

Abbreviations which are used in the descriptions of the schemes,preparations and the examples that follow are:

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

EtOAc: Ethyl acetate

AcOH: Acetic acid

HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one

EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

NMM: N-Methylmorpholine

ADDP: 1,1′-(Azodicarbobyl)dipiperidine

DEAD: Diethylazodicarboxylate

MeOH: Methanol

EtOH: Ethanol

Et2O: Diethyl ether

DMSO: Dimethylsulfoxide

HOBt: N-Hydroxybenzotriazole

PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate

DCM: Dichloromethane

DCC: 1,3-Dicyclohexylcarbodiimide

TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy

Phg: Phenylglycine

Chg: Cyclohexylglycine

Bn: Benzyl

Bzl: Benzyl

Et: Ethyl

Ph: Phenyl

iBoc: isobutoxycarbonyl

iPr: isopropyl

^(t)Bu or Bu^(t): tert-Butyl

Boc: tert-Butyloxycarbonyl

Cbz: Benzyloxycarbonyl

Cp: Cylcopentyldienyl

Ts: p-toluenesulfonyl

Me: Methyl

HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

DMAP: 4-N,N-Dimethylaminopyridine

BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate

PCC: Pyridiniumchlorochromate

KHMDS: Potassium Hexamethyldisilazide or Potassiumbis(trimethylsilylamide)

NaHMDS: Sodium Hexamethyldisilazide or Sodium bis(trimethylsilylamide)

LiHMDS: Lithium Hexamethyldisilazide or Lithium bis(trimethylsilylamide)

10% Pd/C: 10% Palladium on carbon (by weight).

TG: Thioglycerol

General Schemes for Preparation of Target Compounds

Compounds of the present invention were synthesized using the generalschemes (Methods A-E) described below.

Method A

Deprotection of the N-Boc functionality of 1.01 under acidic conditionsprovided the hydrochloride salt 1.02 which was subsequently coupled withN-Boc-tert-leucine under peptide coupling methodology to afford 1.03.N-Boc deprotection followed by treatment with appropriate isocyanategave the urea 1.05. Hydrolysis of the methyl ester provided the acid1.06. Peptide coupling of the acid 1.06 with the appropriate P₁-P′primary amide moiety afforded the hydroxylamide 1.07. Oxidation (Moffattoxidation or related process—see, T. T. Tidwell, Synthesis, 1990, 857),or Dess-Martin Periodinane—J. Org. Chem., (1983) 48, 4155) resulted inthe target compound 1.08.

Peptide coupling of the acid 1.06 with the appropriate P₁-P′ secondaryamide moiety afforded the hydroxylamide 1.09. Oxidation (Moffatt orDess-Martin's) resulted in the target compound 1.10.

In another variation, peptide coupling of the N-Boc-P2-P₃-acid 1.17 withthe appropriate P₁-P′ amide moiety afforded the hydroxylamide 1.11.Oxidation (Moffatt or Dess-Martin Periodinane) resulted in the ketoamide 1.12. Deprotection of the N-Boc functionality gave thehydrochloride salt 1.13. Treatment with a suitable isocyanate (orisocyanate equivalent) resulted in the target compound 1.14.

In yet another variation, the hydrochloride salt 1.13 was converted tothe 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenylchloroformate. Subsequent treatment with an amine (or aminehydrochloride salt) of choice provided the target compound 1.14.

In yet another variation, the dipeptide hydrochloride salt 1.03 wasconverted to the 4-nitrophenyl carbamate as described above. Treatmentwith an amine (or amine hydrochloride salt) of choice provided the ureaderivative 1.05. Hydrolysis and further elaboration as described inMethods A/B provided the target compounds 1.14.

The Following Experimental Section Applies for the Preparation of theCompounds of Formula XVIII:

Example 3 Preparation of Compound of Formula 3

To a cooled solution (0° C.) of the intermediates 1.06 (75.0 mg, 0.2mmol) and 1.09 (100.0 mg, 0.36 mmol) in DMF (5.0 mL) was added HATU(Aldrich, 76.05 mg, 0.20 mmol), followed by DIPEA (0.102 mL, 6 mmol).The reaction mixture was stirred for two days then warmed up to roomtemperature, diluted with ethyl acetate (40.0 mL), washed with 5% KH₂PO₄containing 0.05 vol. of 1M H₃PO₄ and brine. Organic layer was dried overMgSO₄, filtered and concentrated to dryness. Residue was purified oversilica gel using acetone-CH₂Cl₂ (1:9 to 1:1) to get 8.0 mg of product offormula 3 (6.5% yield); LCMS: (590.1).

One skilled in the art would understand that other suitable compounds ofFormula XVIII can be prepared in a similar manner to that disclosedabove.

The Following Experimental Section Applies for the Preparation of theCompounds of Formula XIX:

SYNTHESIS OF PREPARATIVE EXAMPLES Synthesis of Example 101

To a stirred solution of the proline derivative 1.01 (3.66 mmol,prepared as described above) in dichloromethane (20 mL) and DMF (15 mL)at 0° C. was added L-boc-tert-leucine (930 mg, 4.03 mmol), DIPEA (2.02mL, 10.98 mmol) and HATU (1.8 g, 4.76 mmol). After 15 minutes at thattemperature, the reaction flask was stored in the freezer (−20° C.),overnight (16 hr). The reaction mixture was diluted with dichloromethane(80 mL) and washed with saturated sodium bicarbonate solution (80 mL),10% aq. citric acid solution (80 mL), brine (80 mL), dried (Na₂SO₄),filtered and concentrated. The crude material was purified by silicachromatography using 25/75 to 50/50 EtOAc/hexanes to provide 1.77 g ofthe required material, 101a. LC-MS: 518.1 (M+H)⁺.

To a solution of the methyl ester 101a (1.21 g, 2.34 mmol) in THF (10mL) and MeOH (5 mL) was added aq. 1M LiOH solution (5 mL). The reactionmixture was stirred at RT for 4 h. It was then concentrated, dilutedwith water (50 mL) and acidified with solid citric acid (pHapproximately 3) when white solid material crashed out. This solid wasfiltered off, washed with water and dried in vacuo to afford 970 mg of101b. LC-MS: 504.1 (M+H)⁺.

The acid 101b (503 mg, 1 mmol) was coupled with intermediate 13.06 (334mg, 1.5 mmol) using essentially procedure described above (Step 1,preparation of 101a) to provide 101c which was used withoutpurification. MS: 672.37 (M+H)⁺.

To a solution of the hydroxyl compound 101c from above indichloromethane (15 mL) was added Dess-Martin's periodinane (848 mg, 2mmol) and the reaction mixture was stirred at RT for 5 h. At this time,the reaction mixture was diluted with dichloromethane (30 mL) and washedwith 1:1 mixture of aq. 10% sodium thiosulfate solution and saturatedsodium bicarbonate solution (2×25 mL each), brine (50 mL), dried(Na₂SO₄), filtered and concentrated. The crude material was purified bysilica chromatography using 15/85 to 50/50 acetone/hexanes to provide410 mg of the required material, 101d. LC-MS: 670.2 (M+H)⁺.

Deprotection of the N-boc functionality of 101d to provide the requiredmaterial 101e was carried out as described for intermediate 1.01, Step 3(reaction time=2 h). LC-MS: 570.1 (M+H)⁺.

To a solution of the amine salt 101e (60 mg, 0.1 mmol) indichloromethane (2 mL) at 0° C. was added DIPEA (0.06 mL, 0.3 mmol)followed by the isocyanate intermediate 65.01 (0.25 M solution intoluene, 0.8 mL, 0.2 mmol). After 15 minutes at that temperature, thereaction flask was stored in the freezer (−20° C.), overnight (16 hr).The reaction mixture was diluted with dichloromethane (20 mL) and washedwith saturated ammonium chloride solution (20 mL), brine (20 mL), dried(Na₂SO₄), filtered and concentrated. The crude material was purified bysilica chromatography using 15/85 to 50/50 acetone/hexanes to providethe required compound 101 (53 mg); LC-MS: 872.2 (M+H)⁺.

One skilled in the art would understand that other suitable compounds ofFormula XIX can be prepared in a similar manner to that disclosed above.

The Following Experimental Section Applies for the Preparation of theCompounds of Formulae Ia, Ib and Ic:

Abbreviations:

Abbreviations which are used in the descriptions of the schemes,preparations and the examples that follow are:

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

EtOAc: Ethyl acetate

AcOH: Acetic acid

HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one

EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

NMM: N-Methylmorpholine

MeOH: Methanol

EtOH: Ethanol

Et2O: Diethyl ether

DMSO: Dimethylsulfoxide

K^(t)BuO: Potassium tert-butoxide

DCM: Dichloromethane

Chg: Cyclohexylglycine

Bn: Benzyl

Et: Ethyl

Ph: Phenyl

iPr: isopropyl

^(t)Bu or Bu^(t): tert-Butyl

Boc: tert-Butyloxycarbonyl

Cbz: Benzyloxycarbonyl

HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate

10% Pd/C: 10% Palladium on carbon (by weight).

EXAMPLE Synthesis of(1R,5S)-N-[3-Amino-1-(Cyclobutylmethyl)-2,3-Dioxopropyl]-3-[2(S)-[[[(1,1-Dimethylethyl)Amino]Carbonyl]Amino]-3,3-Dimethyl-1-Oxobutyl]-6,6-Dimethyl-3-Azabicyclo[3.1.0]Hexan-2(S)-Carboxamide(Structure Ia)

A stirred solution of the ketimime 1a′ (50 g, 187.1 mmol, available fromAldrich Chemical Company, Milwaukee, Wis.) under N₂ in dry THF (400 mL)was cooled to −78° C. and treated with 1 M solution of K-^(t)BuO (220mL, 1.15 equiv.) in THF. The reaction mixture was warmed to 0° C. andstirred for 1 h and treated with bromomethylcyclobutane (28 mL, 249mmol). The reaction mixture was stirred at room temperature for 48 h andconcentrated in vacuo. The residue was dissolved in Et₂O (300 mL) andtreated with aq. HCl (2 M, 300 mL) The resulting solution was stirred atroom temperature for 5 h and extracted with Et₂O (1 L). The aqueouslayer was made basic to pH˜12-14 with aq. NaOH (50%) and extracted withCH₂Cl₂ (3×300 mL). The combined organic layers were dried (MgSO₄),filtered, and concentrated to give pure amine (1b′, 18 g) as a colorlessoil.

A solution of the amine 1b′ (18 g, 105.2 mmol) at 0° C. in CH₂Cl₂ (350mL) was treated with di-tert-butyldicarbonate (23 g, 105.4 mmol) andstirred at rt. for 12 h. After the completion of the reaction (TLC), thereaction mixture was concentrated in vacuo and the residue was dissolvedin THF/H₂O (200 ml, 1:1) and treated with LiOH.H₂O (6.5 g, 158.5 mmol)and stirred at room temperature for 3 h. The reaction mixture wasconcentrated and the basic aqueous layer was extracted with Et₂O. Theaqueous layer was acidified with conc. HCl to pH˜1-2 and extracted withCH₂Cl₂. The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo to yield 1c′ as a colorless viscous oil which wasused for next step without any further purification.

A solution of the acid 1c′ (15.0 g, 62 mmol) in CH₂Cl₂ (250 mL) wastreated with BOP reagent (41.1 g, 93 mmol), N-methylmorpholine (27 mL),N,O-dimethyl hydroxylamine hydrochloride (9.07 g, 93 mmol) and stirredovernight at rt. The reaction mixture was diluted with 1 N aq. HCl (250mL), and the layers were separated and the aqueous layer was extractedwith CH₂Cl₂ (3×300 ml). The combined organic layers were dried (MgSO₄),filtered, concentrated in vacuo and purified by chromatography (SiO₂,EtOAc/Hex 2:3) to yield the amide 1d (15.0 g) as a colorless solid.

A solution of the amide 1d (15 g, 52.1 mmol) in dry THF (200 mL) wastreated dropwise with a solution of LiAlH₄ (1M, 93 mL, 93 mmol) at 0° C.The reaction mixture was stirred at room temperature for 1 h andcarefully quenched at 0° C. with a solution of KHSO₄ (10% aq.) andstirred for 0.5 h. The reaction mixture was diluted with aq. HCl (1 M,150 mL) and extracted with CH₂Cl₂ (3×200 mL), The combined organiclayers were washed with aq. HCl (1 M), saturated NaHCO₃, brine, anddried (MgSO₄). The mixture was filtered and concentrated in vacuo toyield 1e as viscous colorless oil (14 g).

A solution of the aldehyde 1e (14 g, 61.6 mmol) in CH₂Cl₂ (50 mL), wastreated with Et₃N (10.73 mL, 74.4 mmol), and acetone cyanohydrin (10.86g, 127.57 mmol) and stirred at room temperature for 24 hrs. The reactionmixture was concentrated in vacuo and diluted with aq. HCl (1 M, 200 mL)and extracted into CH₂Cl₂ (3×200 mL). The combined organic layer werewashed with H₂O, brine, dried (MgSO₄), filtered, concentrated in vacuoand purified by chromatography (SiO₂, EtOAc/Hex 1:4) to yield 1f (10.3g) as a colorless liquid as a mixture of diastereomers.

Methanol saturated with HCl*, prepared by bubbling HCl gas to CH₃OH (700ml) at 0° C., was treated with cyanohydrin 1f and heated to reflux for24 h. The reaction was concentrated in vacuo to yield 1g, which was usedin the next step without purification.

*Alternatively 6M HCl prepared by addition of AcCl to dry methanol canalso be used.

A solution of the amine hydrochloride 1g in CH₂Cl₂ (200 mL) was treatedwith Et₃N (45.0 mL, 315 mmol) and Boc₂O (45.7 g, 209 mmol) at −78° C.The reaction mixture was then stirred at room temperature overnight anddiluted with HCl (2 M, 200 mL) and extracted into CH₂Cl₂. The combinedorganic layers were dried (MgSO₄) filtered, concentrated in vacuo andpurified by chromatography (EtOAc/Hex 1:4) to yield hydroxy ester 1h.

A solution of methyl ester 1h (3 g, 10.5 mmol) in THF/H₂O (1:1) wastreated with LiOH.H₂O (645 mg, 15.75 mmol) and stirred at rt. for 2 h.The reaction mixture was acidified with aq HCl (1 M, 15 mL) andconcentrated in vacuo. The residue was dried in vacuum.

A solution of the acid in CH₂Cl₂ (50 mL) and DMF (25 mL) was treatedwith NH₄Cl (2.94 g, 5.5 mmol), EDCI (3.15 g, 16.5 mmol), HOOBt (2.69 g,16.5 mmol), and NMM (4.4 g, 44 mmol). The reaction mixture was stirredat room temperature for 3 d. The solvents were removed under vacuo andthe residue was diluted with aq. HCl (250 mL) and extracted with CH₂Cl₂.The combined organic layers were washed with aq. saturated NaHCO₃, dried(MgSO₄) filtered concentrated in vacuo to obtain 1i, which was used asit is in the following steps. (Alternatively 1i can also be obtaineddirectly by the reaction of 1f (4.5 g, 17.7 mmol) with aq. H₂O₂ (10 mL),LiOH.H₂O (820 mg, 20.8 mmol) at 0° C. in 50 mL of CH₃OH for 0.5 h.)

A solution of 1i obtained in the previous step was dissolved in 4 N HClin dioxane and stirred at rt. for 2 h. The reaction mixture wasconcentrated in vacuo to give 1j as a solid, which was used withoutfurther purification.

The amino ester 1l was prepared following the method of R. Zhang and J.S. Madalengoitia (J. Org. Chem. 1999, 64, 330), with the exception thatthe Boc group was cleaved by the reaction of the Boc-protected aminoacid with methanolic HCl.

A solution of Boc-tert-Lue 1k (Fluka, 5.0 g 21.6 mmol) in dry CH₂Cl₂/DMF(50 mL, 1:1) was cooled to 0° C. and treated with the amine 11 (5.3 g,25.7 mmol), NMM (6.5 g, 64.8 mmol) and BOP reagent (11.6 g, 25.7 mmol).The reaction was stirred at rt. for 24 hrs, diluted with aq. HCl (1 M)and extracted with CH₂Cl₂. The combined organic layers were washed withHCl (aq, 1 M), saturated NaHCO₃, brine, dried (MgSO₄), filtered andconcentrated in vacuo and purified by chromatography (SiO₂,acetone/hexane 1:5) to yield 1m as a colorless solid.

A solution of methyl ester 1m (4.0 g, 10.46 mmol) was dissolved in HCl(4 M solution in dioxane) and stirred at rt. for 3 h. The reactionmixture was concentrated in vacuo to obtain the amine hydrochloride saltused in the next step without further purification.

A solution of the amine hydrochloride salt (397 mg, 1.24 mmol) in CH₂Cl₂(10 mL) was cooled to −78° C. and treated with tert-butyl isocyanate(250 mg, 2.5 mmol) and stirred at rt. overnight. The reaction mixturewas concentrated in vacuo and the residue was diluted with aq. HCl (1M)and extracted with CH₂Cl₂. The combined organic layers were washed withaq. HCl (1M), saturated NaHCO₃ and brine. The organic layers were dried,filtered and concentrated in vacuo and the residue was purified bychromatography (SiO₂, acetone/Hex 1:4) to yield 1n as a colorless solid.

A solution of methyl ester 1n (381 mg, 1.0 mmol) in THF/H₂O (1:1, 5 mL)was treated with LiOH.H₂O (62 mg, 1.5 mmol) and stirred at rt. for 3 h.The reaction mixture was acidified with aq. HCl and concentrated invacuo to obtain the free acid.

A solution of acid (254.9 mg, 0.69 mmol) in DMF/CH₂Cl₂ (1:1, 5.0 mL) wastreated with amine 1j (159 mg, 0.763 mmol), EDCI (199 mg, 1.04 mmol),HOOBt (169.5 mg, 1.04 mmol) and NMM (280 mg, 2.77 mmol) at −20° C. Thereaction mixture was stirred at −20° C. for 48 h and concentrated invacuo. The residue was diluted with aq. 1M HCl and extracted with EtOAc,The combined organic layers were extracted with aq. NaHCO₃, aq. HCl,brine, dried (MgSO₄) filtered, concentrated in vacuo to obtain 1o (470mg) as a tan colored solid that was used in the next reaction withoutfurther purification.

A solution of amide 1o (470 mg, 0.9 mmol) in toluene and DMSO (1:1 20mL) at 0° C. was treated with EDCI (1.72 g, 9.0 mmol) and dichloroaceticacid (0.37 mL, 4.5 mmol) and stirred at 0° C. for 4 hrs. The reactionmixture was diluted with CH₂Cl₂, and washed with saturated NaHCO₃, andbrine. The organic layer was dried (MgSO₄), filtered, concentrated, invacuo and purified by chromatography (SiO₂, acetone/hexanes 3:7) toyield 1a as a colorless solid.Separation of the Compound of Formula 1 into Diastereomers of FormulasIb and Ic:

Preparative HPLC Condition for Separation

-   COLUMN USED: NORMAL PHASE YMC DIOL-NP COLUMN 120 Å, S-10/20; 50    mm×500 mm I.D/length-   SOLVENT A: Hexanes-   SOLVENT B: To make 4 L of solvent (1.7 L Isopropanol+300 mL of    CH₃CN+2 L of CH₂Cl₂)-   HPLC CONDITIONS: 12% of Solvent B/88% of Solvent A-   FLOW: 120 mL/min    Procedure: 1 g of compound 1a was dissolved in 10 mL of CH₂Cl₂/25 mL    of Hexanes and injected into the column. It was eluted with 120    mL/min and two peaks were independently collected and concentrated.    The solid residue was further dried in high vacuum and analyzed by    analytical HPLC. Since the polar (second isomer) contained 2.6% of    nonpolar diastereomer (First isomer), it was purified once more to    isolate the pure diastereomers.

Analytical Conditions for Analysis of Diastereomeric Purity

-   COLUMN USED: NORMAL PHASE YMC DIOL-NP COLUMN 200 Å, S-5 □M; 150 mm×3    mm length/I.D-   SOLVENT A: Hexanes-   SOLVENT B: To make 4 L of solvent (1.7 L Isopropanol+300 mL of    CH₃CN+2 L of CH₂Cl₂)-   HPLC CONDITIONS: 8.5% of Solvent B/91.5% of Solvent A-   FLOW: 0.7 mL/min-   Rt    -   Nonpolar isomer (compound Ib)=13.2 min    -   Polar isomer (compound Ic)=16.1 min        2.5 mg of compound in 1 mL was used and 20 μL was injected and        analyzed with a U.V detector at λ=254 nm.        Analytical Data for Compounds 2 and 3.        Compound 3 [Polar Diastereomer]

¹H NMR (d₆-dmso, 500 MHz): δ 8.26 (d, 1H, J=7.0 Hz), 8.00 (s, 1H), 7.75(s, 1H), 5.96 (s, 1H), 5.84 (d, 1H, J=10 Hz), 4.96 (m, 1H), 4.28 (s,1H), 4.11 (d, 1H, J=11.0 Hz), 3.94 (d, 1H, J=10 Hz), 3.73 (dd, 1H, J=10& 5 Hz), 2.48 (m, 1H), 1.95 (m, 2H), 1.61 (m, 1H), 1.59 (m, 1H), 1.77(m,1H), 1.57 (m, 1H), 1.74 (m, 2H), 1.42 (dd, 1H, J=7.5 & 5 Hz), 1.28 (d,1H, J=7.5 Hz), 1.17 (s, 9H), 1.01 (s, 3H), 0.90 (s, 9H), 0.85 (s, 3H).¹³C NMR (d₆-dmso, 125 MHz): δ 197.8, 170.9, 170.8, 162.8, 157.4, 59.1,56.8, 51.8, 48.9, 47.4, 36.7, 34.0, 32.0, 30.6, 29.1, 27.8, 27.3, 27.1,26.4, 26.1, 18.5, 17.7, 12.5. MS [FAB] 520 (55), 421 (100), 308 (75),213 (90). HRMS calcd for C₂₇H₄₆O₅N₅ [M+1]⁺ 520.3499; observed: 520.3505.

Compound 2 [Non-Polar Diastereomer]

¹H NMR (d₆-dmso, 500 MHz): □ 8.15 (d, 1H, J=7.0 Hz), 7.96 (s, 1H), 7.74(s, 1H), 5.96 (s, 1H), 5.86 (d, 1H, J=10 Hz), 4.85 (m, 1H), 4.27 (s,1H), 4.13 (d, 1H, J=11.0 Hz), 3.97 (d, 1H, J=10 Hz), 3.76 (dd, 1H, J=10& 5 Hz), 2.36 (m, 1H), 1.97 (m, 2H), 1.60 (m, 2H), 1.78 (m, 1H), 1.64(m, 1H), 1.75 (m, 2H), 1.44 (dd, 1H, J=7.5 & 5 Hz), 1.27 (d, 1H, J=7.5Hz), 1.17 (s, 9H), 1.00 (s, 3H), 0.89 (s, 9H), 0.82 (s, 3H).

¹³C NMR (d₆-dmso 125 MHz: δ197.1, 171.1, 170.7, 163.0, 157.3, 59.4,56.9, 52.1, 48.9, 47.4, 36.6, 34.0, 32.1, 30.5, 29.1, 27.9, 27.4, 26.8,26.4, 26.1, 18.5, 17.8, 12.4. MS [FAB] 520 (40), 421 (100), 308 (60),213 (65). HRMS calcd. for C₂₇H₄₆O₅N₅ [M+1]⁺ 520.3499; observed:520.3514.

Example 1

Subjects infected with HCV were put on various treatment regimensincluding 200 mg bid, 400 mg bid and 400 mg tid to determine dose andtiming of dose on virus levels in serum. Blood samples were collectedevery [ ] hours and analyzed using reverse transcription PCR methods todetermine viral load. Data on viral load is presented in FIG. 1. Asshown in FIG. 1, overall viral load declined in all three regimens, withcyclical fluctuations in viral load corresponding to the subjects'sleep/wake cycle seen throughout the decline.

Example 2

Healthy subjects were dosed with two regimens of 400 mg. of a compoundof Formula 1a, twice per day (bid) or three times per day (tid) for aperiod of two weeks. Blood samples were taken on day 14 in the morningat time zero (pre-dose) and at 12 hours post-dose (for the bid regimen)or 8 hours post-dose (for the tid regimen). Results are presented inFIG. 2. As shown in the box plots, with tid dosing a metabolism effectis observed. Serum levels of the drug are higher at time zero, 8 hoursafter the previous evening dose, as compared to serum levels of the drugwhen measured 8 hours following the morning dose.

1. A method of treating, preventing or ameliorating one or more symptomsof hepatitis C in a subject comprising the step of administering atleast compound selected from the group consisting of compounds ofFormulae I to XXVI below in combination with food: a. Formula I

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinin Formula I above: Y is selected from the group consisting of thefollowing moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy,aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe optionallysubstituted with X¹¹ or X¹²; X¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with theproviso that X¹¹ may be additionally optionally substituted with X¹²;X¹² is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²; R¹is COR⁵, wherein R⁵ is COR⁷ wherein R⁷ is NHR⁹, wherein R⁹ is selectedfrom the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl,cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl,[CH(R^(1′))]_(p)COOR¹¹, [CH(R^(1′))]_(p)CONR¹²R¹³,[CH(R^(1′))]_(p)SO₂R¹¹, [CH(R^(1′))]_(p)COR¹¹,[CH(R^(1′))]_(p)CH(OH)R¹¹, CH(R^(1′))CONHCH(R²)COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONR¹²R¹³, CH(R^(1′))CONHCH(R²)R′,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))COOR¹¹andCH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))CONR¹²R¹³,wherein R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), R¹¹, R¹², R¹³, and R′are independently selected from the group consisting of H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl,aryl-alkyl and heteroaralkyl; Z is selected from O, N, CH or CR; W maybepresent or absent, and if W is present, W is selected from C═O, C═S,C(═N—CN), or SO₂; Q maybe present or absent, and when Q is present, Q isCH, N, P, (CH₂)_(p), (CHR)_(p), (CRR′)_(p), O, NR, S, or SO₂; and when Qis absent, M may be present or absent; when Q and M are absent, A isdirectly linked to L; A is O, CH₂, (CHR)_(p), (CHR—CHR′)_(p),(CRR′)_(p), NR, S, SO₂ or a bond; E is CH, N, CR, or a double bondtowards A, L or G; G may be present or absent, and when G is present, Gis (CH₂)_(p), (CHR)_(p), or (CRR′)_(p); and when G is absent, J ispresent and E is directly connected to the carbon atom in Formula I as Gis linked to; J may be present or absent, and when J is present, J is(CH₂)_(p), (CHR)_(p), or (CRR′)_(p), SO₂, NH, NR or O; and when J isabsent, G is present and E is directly linked to N shown in Formula I aslinked to J; L may be present or absent, and when L is present, L is CH,CR, O, S or NR; and when L is absent, then M may be present or absent;and if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; M may be present or absent, and when M is present, M is O, NR, S,SO₂, (CH₂)_(p), (CHR)_(p)(CHR—CHR′)_(p), or (CRR′)_(p); p is a numberfrom 0 to 6; and R, R′, R², R³ and R⁴ are independently selected fromthe group consisting of H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₃-C₈cycloalkyl; C₃-C₈ heterocycloalkyl, alkoxy, aryloxy, alkylthio,arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone,aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms; aryl;heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl,heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl moieties may be optionally and chemically-suitablysubstituted, with said term “substituted” referring to optional andchemically-suitable substitution with one or more moieties selected fromthe group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl,cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy,alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate,urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone,sulfonyl urea, hydrazide, and hydroxamate; further wherein said unitN—C-G-E-L-J-N represents a five-membered or six-membered cyclic ringstructure with the proviso that when said unit N—C-G-E-L-J-N representsa five-membered cyclic ring structure, or when the bicyclic ringstructure in Formula I comprising N, C, G, E, L, J, N, A, Q, and Mrepresents a five-membered cyclic ring structure, then saidfive-membered cyclic ring structure lacks a carbonyl group as part ofthe cyclic ring; b. Formula II

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula II above: Z is NH; X is alkylsulfonyl, heterocyclylsulfonyl,heterocyclylalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,alkyaminocarbonyl, heterocyclylaminocarbonyl, arylaminocarbonyl, orheteroarylaminocarbonyl moiety, with the proviso that X may beadditionally optionally substituted with R¹² or R¹³; X¹ is H; C₁-C₄straight chain alkyl; C₁-C₄ branched alkyl or; CH₂-aryl (substituted orunsubstituted); R¹² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl moiety, withthe proviso that R¹² may be additionally optionally substituted withR¹³. R¹³ is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitromoiety, with the proviso that the alkyl, alkoxy, and aryl may beadditionally optionally substituted with moieties independently selectedfrom R¹³. P1a, P1b, P2, P3, P4, P5, and P6 are independently: H; C1-C10straight or branched chain alkyl; C2-C10 straight or branched chainalkenyl; C3-C8 cycloalkyl, C3-C8 heterocyclic; (cycloalkyl)alkyl or(heterocyclyl)alkyl, wherein said cycloalkyl is made up of 3 to 8 carbonatoms, and zero to 6 oxygen, nitrogen, sulfur, or phosphorus atoms, andsaid alkyl is of 1 to 6 carbon atoms; aryl, heteroaryl, arylalkyl, orheteroarylalkyl, wherein said alkyl is of 1 to 6 carbon atoms; whereinsaid alkyl, alkenyl, cycloalkyl, heterocyclyl; (cycloalkyl)alkyl and(heterocyclyl)alkyl moieties may be optionally substituted with R¹³, andfurther wherein said P1a and P1b may optionally be joined to each otherto form a spirocyclic or spiroheterocyclic ring, with said spirocyclicor spiroheterocyclic ring containing zero to six oxygen, nitrogen,sulfur, or phosphorus atoms, and may be additionally optionallysubstituted with R¹³; and P1′ is H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclyl-alkyl, aryl, aryl-alkyl,heteroaryl, or heteroaryl-alkyl; with the proviso that said P1′ may beadditionally optionally substituted with R¹³; c. Formula III

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula III above: G is carbonyl; J and Y may be the same ordifferent and are independently selected from the group consisting ofthe moieties: H, alkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy,aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe additionallyoptionally substituted with X¹¹ or X¹²; X¹¹ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl moiety, with the proviso that X¹¹may be additionally optionally substituted with X¹²; X¹² is hydroxy,alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino,arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²; R¹is COR⁵ or B(OR)₂, wherein R⁵ is selected from the group consisting ofH, OH, OR⁸, NR⁹R¹⁰, CF₃, C₂F₅, C₃F₇, CF₂R⁶, R⁶ and COR⁷ wherein R⁷ isselected from the group consisting of H, OH, OR⁸, CHR⁹R¹⁰, and NR⁹R¹⁰,wherein R⁶, R⁸, R⁹ and R¹⁰ may be the same or different and areindependently selected from the group consisting of H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl,heteroarylalkyl, CH(R^(1,))COOR¹¹, CH(R^(1,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))COOR¹¹, CH(R^(1′))CONHCH(R^(2,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))R′,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))COOR¹¹,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))COOR¹¹,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4′))CONHCH(R^(5,))COOR¹¹,andCH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))CONHCH(R^(5,))CONR¹²R¹³,wherein R^(1,), R^(2,), R^(3,), R^(4,), R^(5,), R¹¹, R¹², R¹³, and R′may be the same or different and are independently selected from a groupconsisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl,alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; Z isselected from O, N, or CH; W maybe present or absent, and if W ispresent, W is selected from C═O, C═S, or SO₂; and R, R′, R², R³ and R⁴are independently selected from the group consisting of H; C1-C10 alkyl;C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro; oxygen, nitrogen,sulfur, or phosphorus atoms (with said oxygen, nitrogen, sulfur, orphosphorus atoms numbering zero to six); (cycloalkyl)alkyl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms; aryl;heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl,heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl moieties may be optionally substituted, with said term“substituted” referring to optional and chemically-suitable substitutionwith one or more moieties selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen,hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido,ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,sulfonamide, sulfoxide, sulfone, sulfonylurea, hydrazide, andhydroxamate; d. Formula IV

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: Y is selected from the group consisting of the followingmoieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe optionallysubstituted with X¹¹ or X¹²; X¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with theproviso that X¹¹ may be additionally optionally substituted with X¹²;X¹² is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²; R¹is selected from the following structures:

wherein k is a number from 0 to 5, which can be the same or different,R¹¹ denotes optional substituents, with each of said substituents beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, cycloalkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino,heterocycloalkylamino, hydroxy, thio, alkylthio, arylthio, amino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido,carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, and nitro,with the proviso that R¹¹ (when R¹¹≠H) maybe optionally substituted withX¹¹ or X¹²; Z is selected from O, N, CH or CR; W may be present orabsent, and if W is present, W is selected from C═O, C═S, C(═N—CN), orS(O₂); Q may be present or absent, and when Q is present, Q is CH, N, P,(CH₂)_(p), (CHR)_(p), (CRR′)_(p), O, N(R), S, or S(O₂); and when Q isabsent, M may be present or absent; when Q and M are absent, A isdirectly linked to L; A is O, CH₂, (CHR)_(p), (CHR—CHR′)_(p),(CRR′)_(p), N(R), S, S(O₂) or a bond; E is CH, N, CR, or a double bondtowards A, L or G; G may be present or absent, and when G is present, Gis (CH₂)_(p), (CHR)_(p), or (CRR′)_(p); and when G is absent, J ispresent and E is directly connected to the carbon atom in Formula I as Gis linked to; J may be present or absent, and when J is present, J is(CH₂)_(p), (CHR)_(p), or (CRR′)_(p), S(O₂), NH, N(R) or O; and when J isabsent, G is present and E is directly linked to N shown in Formula I aslinked to J; L may be present or absent, and when L is present, L is CH,C(R), O, S or N(R); and when L is absent, then M may be present orabsent; and if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; M may be present or absent, and when M is present, M is O, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p)(CHR—CHR′)_(p), or (CRR′)_(p); p is a numberfrom 0 to 6; and R, R′, R², R³ and R⁴ can be the same or different, eachbeing independently selected from the group consisting of H; C₁-C₁₀alkyl; C₂-C₁₀ alkenyl; C₃-C₈ cycloalkyl; C₃-C₈ heterocycloalkyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro, halogen,(cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkylis made of three to eight carbon atoms, and zero to six oxygen,nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to sixcarbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionallysubstituted, with said term “substituted” referring to substitution withone or more moieties which can be the same or different, each beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy,thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester,carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, andhydroxamate; further wherein said unit N—C-G-E-L-J-N represents afive-membered cyclic ring structure or six-membered cyclic ringstructure with the proviso that when said unit N—C-G-E-L-J-N representsa five-membered cyclic ring structure, or when the bicyclic ringstructure in Formula I comprising N, C, G, E, L, J, N, A, Q, and Mrepresents a five-membered cyclic ring structure, then saidfive-membered cyclic ring structure lacks a carbonyl group as part ofsaid five-membered cyclic ring. e) Formula V

or a pharmaceutically acceptable salt, solvate or ester of said compoundwherein: (1) R¹ is —C(O)R⁵ or —B(OR)₂; (2) R⁵ is H, —OH, —OR⁸, —NR⁹R¹⁰,—C(O)OR⁸, —C(O)NR⁹R¹⁰, —CF₃, —C₂F₅, C₃F₇, —CF₂R⁶, —R⁶, —C(O)R⁷ orNR⁷SO₂R⁸; (3) R⁷ is H, —OH, —OR⁸, or —CHR⁹R¹⁰; (4) R⁶, R⁸, R⁹ and R¹⁰are independently selected from the group consisting of H: alkyl,alkenyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl,heteroarylalkyl, R¹⁴, —CH(R^(1′))CH(R^(1′))C(O)OR¹¹,[CH(R^(1′))]_(p)C(O)OR¹¹, —[CH(R^(1′))]_(p)C(O)NR¹²R¹³,—[CH(R^(1′))]_(p)S(O₂)R¹¹, —[CH(R^(1′))]_(p)C(O)R¹¹,—[CH(R^(1′))]_(p)S(O₂)NR¹²R¹³, CH(R^(1′))C(O)N(H)CH(R^(2′))(R′),CH(R^(1′))CH(R^(1′))C(O)NR¹²R¹³, —CH(R^(1′))CH(R^(1′))S(O₂)R¹¹,—CH(R^(1′))CH(R^(1′))S(O₂)NR¹²R¹³, —CH(R^(1′))CH(R^(1′))C(O)R¹¹,—[CH(R^(1′))]_(p)CH(OH)R¹¹, —CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)OR¹¹,C(O)N(H)CH(R^(2′))C(O)OR¹¹, —C(O)N(H)CH(R^(2′))C(O)R¹¹,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)NR¹²R¹³,—CH(R^(1′))C(O)N(H)CH(R^(2′))R′,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)OR¹¹,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)CH(R^(3′))NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)OR¹¹,H(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)N(H)CH(R^(5′))C(O)OR¹¹,andCH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)N(H)CH(R^(5′))C(O)NR¹²R¹³;wherein R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), R¹¹, R¹² and R¹³ can bethe same or different, each being independently selected from the groupconsisting of: H, halogen, alkyl, aryl, heteroalkyl, heteroaryl,cycloalkyl, alkoxy, aryloxy, alkenyl, alkynyl, alkyl-aryl,alkyl-heteroaryl, heterocycloalkyl, aryl-alkyl and heteroaralkyl; or R¹²and R¹³ are linked together wherein the combination is cycloalkyl,heterocycloalkyl, ary or heteroaryl; R¹⁴ is present or not and ifpresent is selected from the group consisting of: H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, allyl,alkyl-heteroaryl, alkoxy, aryl-alkyl, alkenyl, alkynyl andheteroaralkyl; (5) R and R′ are present or not and if present can be thesame or different, each being independently selected from the groupconsisting of: H, OH, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₃-C₈ cycloalkyl,C₃-C₈ heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio,alkylamino, arylamino, amino, amido, arylthioamino, arylcarbonylamino,arylaminocarboxy, alkylaminocarboxy, heteroalkyl, alkenyl, alkynyl,(aryl)alkyl, heteroarylalkyl, ester, carboxylic acid, carbamate, urea,ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl, aryl,heteroaryl, (alkyl)aryl, alkylheteroaryl, alkyl-heteroaryl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms; (6) L′is H, OH, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, orheterocyclyl; (7) M′ is H, alkyl, heteroalkyl, aryl, heteroaryl,cycloalkyl, arylalkyl, heterocyclyl or an amino acid side chain; or L′and M′ are linked together to form a ring structure wherein the portionof structural Formula 1 represented by

is represented by structural Formula 2:

wherein in Formula 2: E is present or absent and if present is C, CH, Nor C(R); J is present or absent, and when J is present, J is (CH₂)_(p),(CHR—CHR′)_(p), (CHR)_(p), (CRR′)_(p), S(O₂), N(H), N(R) or O; when J isabsent and G is present, L is directly linked to the nitrogen atommarked position 2; p is a number from 0 to 6; L is present or absent,and when L is present, L is C(H) or C(R); when L is absent, M is presentor absent; if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; G is present or absent, and when G is present, G is (CH₂)_(p),(CHR)_(p), (CHR—CHR′)_(p) or (CRR′)_(p); when G is absent, J is presentand E is directly connected to the carbon atom marked position 1; Q ispresent or absent, and when Q is present, Q is NR, PR, (CR═CR),(CH₂)_(p), (CHR)_(p), (CRR′)_(p), (CHR—CHR′)_(p), O, NR, S, SO, or SO₂;when Q is absent, M is (i) either directly linked to A or (ii) anindependent substituent on L, said independent substituent bing selectedfrom —OR, —CH(R)(R′), S(O)₀₋₂R or —NRR′ or (iii) absent; when both Q andM are absent, A is either directly linked to L, or A is an independentsubstituent on E, said independent substituent bing selected from —OR,—CH(R)(R′), S(O)₀₋₂R or —NRR′ or A is absent; A is present or absent andif present A is O, O(R), (CH₂)_(p), (CHR)_(p), (CHR—CHR′)_(p),(CRR′)_(p), N(R), NRR′, S, S(O₂), —OR, CH(R)(R′) or NRR′; or A is linkedto M to form an alicyclic, aliphatic or heteroalicyclic bridge; M ispresent or absent, and when M is present, M is halogen, O, OR, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p)(CHR—CHR′)_(p), or (CRR′)_(p); or M is linkedto A to form an alicyclic, aliphatic or heteroalicyclic bridge; (8) Z′is represented by the structural Formula 3:

wherein in Formula 3, Y is selected from the group consisting of: H,aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, heteroalkyl-heteroaryl,heteroalkyl-heterocycloalkyl, cycloalkyloxy, alkylamino, arylamino,alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino andheterocycloalkylamino, and Y is unsubstituted or optionally substitutedwith one or two substituents which are the same or different and areindependently selected from X¹¹ or X¹²; X¹¹ is alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl,alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl,and X¹¹ is unsubstituted or optionally substituted with one or more ofX¹² moieties which are the same or different and are independentlyselected; X¹² is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl,aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,carbalkoxy, carboxamido, alkylcarbonyl, arylcarbonyl,heteroalkylcarbonyl, heteroarylcarbonyl, sulfonylurea,cycloalkylsulfonamido, heteroaryl-cycloalkylsulfonamido,heteroaryl-sulfonamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halogen, cyano, or nitro, and said alkyl,alkoxy, and aryl are unsubstituted or optionally independentlysubstituted with one or more moieties which are the same or differentand are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl; Z is O, N,C(H) or C(R); R³¹ is H, hydroxyl, aryl, alkyl, alkyl-aryl, heteroalkyl,heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy,alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy,heteroalkyl-heteroaryl, cycloalkyloxy, alkylamino, arylamino,alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino orheterocycloalkylamino, and R³¹ is unsubstituted or optionallysubstituted with one or two substituents which are the same or differentand are independently selected from X¹³ or X¹⁴; X¹³ is alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl,aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, orheteroarylalkyl, and X¹³ is unsubstituted or optionally substituted withone or more of X¹⁴ moieties which are the same or different and areindependently selected; X¹⁴ is hydroxy, alkoxy, alkyl, alkenyl, alkynyl,aryl, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,carbalkoxy, carboxamido, alkylcarbonyl, arylcarbonyl,heteroalkylcarbonyl, heteroarylcarbonyl, cycloalkylsulfonamido,heteroarylcycloalkylsulfonamido, heteroarylsulfonamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,halogen, cyano, or nitro, and said alkyl, alkoxy, and aryl areunsubstiuted or optionally independently substituted with one or moremoieties which are the same or different and are independently selectedfrom alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl; W may be present or absent, and ifW is present, W is C(═O), C(═S), C(═N—CN), or S(O₂); (9) X isrepresented by structural Formula 4:

wherein in Formula 4, a is 2, 3, 4, 5, 6, 7, 8 or 9; b, c, d, e and fare 0, 1, 2, 3, 4 or 5; A is C, N, S or O; R²⁹ and R^(29′) areindependently present or absent and if present can be the same ordifferent, each being independently one or two substituentsindependently selected from the group consisting of: H, halo, alkyl,aryl, cycloalkyl, cycloalkylamino, cycloalkylaminocarbonyl, cyano,hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, carboxyl, C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl,aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl,hydroxyalkyl, aryloxy, aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl,heterocyclyl, heterocyclenyl, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—,wherein Y₁ and Y₂ can be the same or different and are independentlyselected from the group consisting of hydrogen, alkyl, aryl, andaralkyl; or R²⁹ and R^(29′) are linked together such that thecombination is an aliphatic or heteroaliphatic chain of 0 to 6 carbons;R³⁰ is present or absent and if present is one or two substituentsindependently selected from the group consisting of: H, alkyl, aryl,heteroaryl and cylcoalkyl; (10) D is represented by structural Formula5:

wherein in Formula 5, R³², R³³ and R³⁴ are present or absent and ifpresent are independently one or two substituents independently selectedfrom the group consisting of: H, halo, alkyl, aryl, cycloalkyl,cycloalkylamino, spiroalkyl, cycloalkylaminocarbonyl, cyano, hydroxy,alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂,carboxyl, —C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl, aralkenyl,heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxyalkyl, aryloxy,aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl,arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkenyl, heterocyclyl, heterocyclenyl,Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ can be thesame or different and are independently selected from the groupconsisting of hydrogen, alkyl, aryl, and aralkyl; or R³² and R³⁴ arelinked together such that the combination forms a portion of acycloalkyl group; g is 1, 2, 3, 4, 5, 6, 7, 8 or 9; h, i, j, k, l and mare 0, 1, 2, 3, 4 or 5; and A is C, N, S or O, (11) provided that whenstructural Formula 2:

W′ is CH or N, both the following conditional exclusions (i) and (ii)apply: conditional exclusion (i): Z′ is not —NH—R³⁶, wherein R³⁶ is H,C_(6 or 10) aryl, heteroaryl, —C(O)—R³⁷, —C(O)—OR³⁷ or —C(O)—NHR³⁷,wherein R³⁷ is C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and conditional exclusion(ii): R¹ is not —C(O)OH, a pharmaceutically acceptable salt of —C(O)OH,an ester of —C(O)OH or —C(O)NHR³⁸ wherein R³⁸ is selected from the groupconsisting of C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C_(6 to 10) aryl or C₇₋₁₆aralkyl. f. Formula VI

or a pharmaceutically acceptable salt, solvate or ester of saidcompound, wherein in Formula VI above: Cap is H, alkyl, alkyl-aryl,heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl,alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy,cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy orheterocyclylamino, wherein each of said alkyl, alkyl-aryl, heteroalkyl,heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy,alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy,amino, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy orheterocyclylamino can be unsubstituted or optionally independentlysubstituted with one or two substituents which can be the same ordifferent and are independently selected from X¹ and X²; P′ is —NHR; X¹is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl,heteroaryl, heterocyclylamino, alkylheteroaryl, or heteroarylalkyl, andX¹ can be unsubstituted or optionally independently substituted with oneor more of X² moieties which can be the same or different and areindependently selected; X² is hydroxy, alkyl, aryl, alkoxy, aryloxy,thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halogen, cyano, keto, ester or nitro, wherein each of saidalkyl, alkoxy, and aryl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same or differentand are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino,alkylheteroaryl and heteroarylalkyl; W may be present or absent, andwhen W is present W is C(═O), C(═S), C(═NH), C(═N—OH), C(═N—CN), S(O) orS(O₂); Q maybe present or absent, and when Q is present, Q is N(R),P(R), CR═CR′, (CH₂)_(p), (CHR)_(p), (CRR′)_(p), (CHR—CHR′)_(p), O, S,S(O) or S(O₂); when Q is absent, M is (i) either directly linked to A or(ii) M is an independent substituent on L and A is an independentsubstituent on E, with said independent substituent being selected from—OR, —CH(R′), S(O)₀₋₂R or —NRR′; when both Q and M are absent, A iseither directly linked to L, or A is an independent substituent on E,selected from —OR, CH(R)(R′), —S(O)₀₋₂R or —NRR′; A is present or absentand if present A is —O—, —O(R)CH₂—, —(CHR)_(p)—, —(CHR—CHR′)_(p)—,(CRR′)_(p), N(R), NRR′, S, or S(O₂), and when Q is absent, A is —OR,—CH(R)(R′) or —NRR′; and when A is absent, either Q and E are connectedby a bond or Q is an independent substituent on M; E is present orabsent and if present E is CH, N, C(R); G may be present or absent, andwhen G is present, G is (CH₂)_(p), (CHR)_(p), or (CRR′)_(p); when G isabsent, J is present and E is directly connected to the carbon atommarked position 1; J may be present or absent, and when J is present, Jis (CH₂)_(p), (CHR—CHR′)_(p), (CHR)_(p), (CRR′)_(p), S(O₂), N(H), N(R)or O; when J is absent and G is present, L is directly linked to thenitrogen atom marked position 2; L may be present or absent, and when Lis present, L is CH, N, or CR; when L is absent, M is present or absent;if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; M may be present or absent, and when M is present, M is O, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p), (CHR—CHR′)_(p), or (CRR′)_(p); p is anumber from 0 to 6; R, R′ and R³ can be the same or different, eachbeing independently selected from the group consisting of: H, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, arylthioamino,arylcarbonylamino, arylaminocarboxy, alkylaminocarboxy, heteroalkyl,heteroalkenyl, alkenyl, alkynyl, aryl-alkyl, heteroarylalkyl, ester,carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,halogen, (cycloalkyl)alkyl, aryl, heteroaryl, alkyl-aryl,alkylheteroaryl, alkyl-heteroaryl and (heterocyclyl)alkyl; R and R′ in(CRR′) can be linked together such that the combination forms acycloalkyl or heterocyclyl moiety; and R¹ is carbonyl;

Formula VII or a pharmaceutically acceptable salt, solvate or esterthereof, wherein, M is O, N(H), or CH₂; n is 0-4; R¹ is —OR⁶, —NR⁶R⁷ or

where R⁶ and R⁷ can be the same or different, each being independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino,arylamino and alkylamino; R⁴ and R⁵ can be the same or different, eachbeing independently selected from the group consisting of H, alkyl, aryland cycloalkyl; or alternatively R⁴ and R⁵ together form part of acyclic 5- to 7-membered ring such that the moiety

is represented by

where k is 0 to 2; X is selected from the group consisting of:

where p is 1 to 2, q is 1-3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and R³ is selected from the group consisting of: aryl,heterocyclyl, heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy. h. Formula VIII

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinin Formula VIII above, M is O, N(H), or CH₂; R¹ is —C(O)NHR⁶, where R⁶is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, hydroxyl, amino, arylamino oralkylamino; P₁ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl haloalkyl; P₃ is selected from the group consistingof alkyl, cycloalkyl, aryl and cycloalkyl fused with aryl; R⁴ and R⁵ canbe the same or different, each being independently selected from thegroup consisting of H, alkyl, aryl and cycloalkyl; or alternatively R⁴and R⁵ together form part of a cyclic 5- to 7-membered ring such thatthe moiety

is represented by

where k is 0 to 2; X is selected from the group consisting of:

where p is 1 to 2, q is 1 to 3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and R³ is selected from the group consisting of: aryl,heterocyclyl, heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy; i. formula IX:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein, M is O, N(H), or CH₂; n is 0-4; R¹ is —OR⁶, —NR⁶R⁷ or

where R⁶ and R⁷ can be the same or different, each being independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino,arylamino and alkylamino; R⁴ and R⁵ can be the same or different, eachbeing independently selected from the group consisting of H, alkyl, aryland cycloalkyl; or alternatively R⁴ and R⁵ together form part of acyclic 5- to 7-membered ring such that the moiety

is represented by

where k is 0 to 2; X is selected from the group consisting of:

where p is 1 to 2, q is 1 to 3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and R³ is selected from the group consisting of: aryl,heterocyclyl, heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy; j. Formula X

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula X above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, R¹⁵ and R¹⁶ are connected to eachother to form a four to eight-membered cycloalkyl, heteroaryl orheterocyclyl structure, and likewise, independently R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; k. Formula XI

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XI above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, NR⁹R¹⁰, SR, SO₂R, and halo; orA and M are connected to each other (in other words, A-E-L-M takentogether) such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NR⁹R¹⁰ forms afour to eight-membered heterocyclyl; Y is selected from the followingmoieties:

wherein Y³⁰ and Y³¹ are selected from

where u is a number 0-6; X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O)and SO₂; G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, T₃ and T₄can be the same or different, each being independently selected from thegroup consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl,alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl, or alternately, R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; l. Formula XII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XII above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, (i) either R¹⁵ and R¹⁶ areconnected to each other to form a four to eight-membered cyclicstructure, or R¹⁵ and R¹⁹ are connected to each other to form a four toeight-membered cyclic structure, and (ii) likewise, independently, R¹⁷and R¹⁸ are connected to each other to form a three to eight-memberedcycloalkyl or heterocyclyl; wherein each of said alkyl, aryl,heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of: □ulfonam, alkoxy, aryloxy, thio,alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, □ulfonamide, alkylsulfonamido, arylsulfonamido, alkyl,aryl, heteroaryl, keto, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo,cyano, and nitro; m. Formula XIII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XIII above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other (in other words, A-E-L-Mtaken together) such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O, and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ can be thesame or different, each being independently selected from the groupconsisting of H, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ heteroalkenyl, C₂-C₁₀ alkynyl, C₂-C₁₀ heteroalkynyl, C₃-C₈cycloalkyl, C₃-C₈ heterocyclyl, aryl, heteroaryl, or alternately: (i)either R¹⁵ and R¹⁶ can be connected to each other to form a four toeight-membered cycloalkyl or heterocyclyl, or R¹⁵ and R¹⁹ are connectedto each other to form a five to eight-membered cycloalkyl orheterocyclyl, or R¹⁵ and R²⁰ are connected to each other to form a fiveto eight-membered cycloalkyl or heterocyclyl, and (ii) likewise,independently, R¹⁷ and R¹⁸ are connected to each other to form a threeto eight-membered cycloalkyl or heterocyclyl, wherein each of saidalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstitutedor optionally independently substituted with one or more moietiesselected from the group consisting of: hydroxy, alkoxy, aryloxy, thio,alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, keto,carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro; n.Formula XIV

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XIV above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

L^(/)-E^(/) shown above in Formula I forms either a three, four, six,seven or eight-membered cycloalkyl, a four to eight-memberedheterocyclyl, a six to ten-membered aryl, or a five to ten-memberedheteroaryl; E is C(H) or C═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R²,and R³ can be the same or different, each being independently selectedfrom the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, or alternately R and R′ inNRR′ are connected to each other such that NRR′ forms a four toeight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, oralternately, (i) R¹⁵ and R¹⁶ are connected to each other to form a fourto eight-membered cyclic structure, and (ii) likewise, independently R¹⁷and R¹⁸ are connected to each other to form a three to eight-memberedcycloalkyl or heterocyclyl; wherein each of said alkyl, aryl,heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, alkyl,aryl, heteroaryl, keto, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo,cyano, and nitro; p. Formula XV

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XV above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, cycloalkyl-, arylalkyl-, orheteroarylalkyl; E and J can be the same or different, each beingindependently selected from the group consisting of R, OR, NHR, NRR⁷,SR, halo, and S(O₂)R, or E and J can be directly connected to each otherto form either a three to eight-membered cycloalkyl, or a three toeight-membered heterocyclyl moiety; Z is N(H), N═, or O, with theproviso that when Z is O, G is present or absent and if G is presentwith Z being O, then G is C(═O); G maybe present or absent, and if G ispresent, G is C(═O) or S(O₂), and when G is absent, Z is directlyconnected to Y; Y is selected from the group consisting of:

R, R⁷, R², R³, R⁴ and R⁵ can be the same or different, each beingindependently selected from the group consisting of H, alkyl-, alkenyl-,alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-, wherein each of said heteroalkyl, heteroaryl andheterocyclyl independently has one to six oxygen, nitrogen, sulfur, orphosphorus atoms; wherein each of said alkyl, heteroalkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl moieties can beunsubstituted or optionally independently substituted with one or moremoieties selected from the group consisting of alkyl, alkenyl, alkynyl,aryl, aralkyl, cycloalkyl, heterocyclyl, halo, hydroxy, thio, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide,sulfone, sulfonyl urea, hydrazide, and hydroxamate; q. Formula XVI

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XVI above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; R² and R³ can be the same or different,each being independently selected from the group consisting of H, alkyl,heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Y isselected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³,R²⁴ and R²⁵ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R¹⁷ andR¹⁸ are independently connected to each other to form a three toeight-membered cycloalkyl or heterocyclyl; (ii) likewise independentlyR¹⁵ and R¹⁹ are connected to each other to form a four to eight-memberedheterocyclyl; (iii) likewise independently R¹⁵ and R¹⁶ are connected toeach other to form a four to eight-membered heterocyclyl; (iv) likewiseindependently R¹⁵ and R²⁰ are connected to each other to form a four toeight-membered heterocyclyl; (v) likewise independently R²² and R²³ areconnected to each other to form a three to eight-membered cycloalkyl ora four to eight-membered heterocyclyl; and (vi) likewise independentlyR²⁴ and R²⁵ are connected to each other to form a three toeight-membered cycloalkyl or a four to eight-membered heterocyclyl;wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro; r. Formula XVII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XVII above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; Y is selected from the followingmoieties:

wherein Y³⁰ is selected from

where u is a number 0-1; X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O)and SO₂; G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, and T₃ canbe the same or different, each being independently selected from thegroup consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl,alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl, or alternately, R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; s. Formula XVIII:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein: R⁸ is selected from the group consisting of alkyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-,heteroarylalkyl-, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl and cycloalkyl; A and Mcan be the same or different, each being independently selected from R,OR, N(H)R, N(RR′), SR, S(O₂)R, and halo; or A and M are connected toeach other (in other words, A-E-L-M taken together) such that themoiety:

shown above in Formula I forms either a three, four, five, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC(R); L is C(H), C(R), CH₂C(R), or C(R)CH₂; R and R′ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in N(RR′) are connected to each other such that N(RR′) forms afour to eight-membered heterocyclyl; R² and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, spiro-linked cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl; Y is selected from thefollowing moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately (i) R¹⁷ and R¹⁸ are independentlyconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; (ii) likewise independently R¹⁵ and R¹⁹ are connected toeach other to form a four to eight-membered heterocyclyl; (iii) likewiseindependently R¹⁵ and R¹⁶ are connected to each other to form a four toeight-membered heterocyclyl; and (iv) likewise independently R¹⁵ and R²⁰are connected to each other to form a four to eight-memberedheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl,spiro-linked cycloalkyl, and heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, sulfonamido, alkyl, alkenyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro. t. Formula XIX

wherein in Formula XIX above: Z is selected from the group consisting ofa heterocyclyl moiety, N(H)(alkyl), —N(alkyl)₂, —N(H)(cycloalkyl),—N(cycloalkyl)₂, —N(H)(aryl, —N(aryl)₂, —N(H)(heterocyclyl),—N(heterocyclyl)₂, —N(H)(heteroaryl), and —N(heteroaryl)₂; R¹ is NHR⁹,wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-, heteroalkyl-,heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, or heteroarylalkyl;R² and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl; Y is selected from thefollowing moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ can bethe same or different, each being independently selected from the groupconsisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately (i) R¹⁷ and R¹⁸ are independentlyconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; (ii) likewise independently R¹⁵ and R¹⁹ are connected toeach other to form a four to eight-membered heterocyclyl; (iii) likewiseindependently R¹⁵ and R¹⁶ are connected to each other to form a four toeight-membered heterocyclyl; and (iv) likewise independently R¹⁵ and R²⁰are connected to each other to form a four to eight-memberedheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; u. Formula XX

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: a is 0 or 1; b is 0 or 1; Y is H or C₁₋₆ alkyl; B is H, an acylderivative of formula R₇—C(O)— or a sulfonyl of formula R₇—SO2 whereinR7 is (i) C_(l-10) alkyl optionally substituted with carboxyl, C₁₋₆alkanoyloxy or C₁₋₆ alkoxy; (ii) C₃₋₇ cycloalkyl optionally substitutedwith carboxyl, (C_(l-6) alkoxy)carbonyl or phenylmethoxycarbonyl; (iii)C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substituted with C₁₋₆ alkyl,hydroxy, or amino optionally substituted with C₁₋₆ alkyl; or (iv) Hetoptionally substituted with C₁₋₆ alkyl, hydroxy, amino optionallysubstituted with C₁₋₆ alkyl, or amido optionally substituted with C₁₋₆alkyl; R₆, when present, is C₁₋₆ alkyl substituted with carboxyl; R₅,when present, is C₁₋₆ alkyl optionally substituted with carboxyl; R₄ isC₁₋₁₀ alkyl, C₃₋₇ cycloalkyl or C₄₋₁₀ (alkylcycloalkyl); R₃ is C₁₋₁₀alkyl, C₃₋₇ cycloalkyl or C₄₋₁₀ (alkylcycloalkyl); R₂ is CH₂—R₂₀,NH—R₂₀, 0-R₂₀ or S—R₂₀, wherein R₂₀ is a saturated or unsaturated C₃₋₇cycloalkyl or C₄₋₁₀ (alkyl cycloalkyl) being optionally mono-, di- ortri-substituted with R₂₁, or R₂₀ is a C₆ or C₁₀ aryl or C₇₋₁₆ aralkyloptionally mono-, di- or tri-substituted with R₂₁, or R₂₀ is Het or(lower alkyl)-Het optionally mono-, di- or tri-substituted with R₂₁,wherein each R₂₁ is independently C₁₋₆ alkyl; C₁₋₆alkoxy; aminooptionally mono- or di-substituted with C₁₋₆ alkyl; sulfonyl; N0₂; OH;SH; halo; haloalkyl; amido optionally mono-substituted with C₁₋₆ alkyl,C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl, Het or (lower alkyl)-Het; carboxyl;carboxy(lower alkyl); C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl or Het, said aryl,aralkyl or Het being optionally substituted with R₂₂; wherein R₂₂ isC₁₋₆alkyl; C₁₋₆ alkoxy; amino optionally mono- or di-substituted withC₁₋₆ alkyl; sulfonyl; N0₂; OH; SH; halo; haloalkyl; carboxyl; amide or(lower alkyl)amide; R₁ is C₁₋₆ alkyl or C₂₋₆ alkenyl optionallysubstituted with halogen; and W is hydroxy or a N-substituted amino. Inthe above-shown structure of the compound of Formula XX, the terms P6,P5, P4, P3, P2 and P1 denote the respective amino acid moieties as isconventionally known to those skilled in the art. v. Formula XXI

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: B is H, a C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl; Het or (loweralkyl)-Het, all of which optionally substituted with C₁₋₆ alkyl; C₁₋₆alkoxy; C₁₋₆ alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro;cyano; cyanoalkyl; amino optionally substituted with C₁₋₆ alkyl; amido;or (lower alkyl)amide; or B is an acyl derivative of formula R₄—C(O)—; acarboxyl of formula R₄-0-C(O)—; an amide of formula R₄—N(R₅)—C(O)—; athioamide of formula R₄—N(R₅)—C(S)—; or a sulfonyl of formula R₄—SO2wherein R₄ is (i) C₁₋₁₀ alkyl optionally substituted with carboxyl, C₁₋₆alkanoyl, hydroxy, C₁₋₆ alkoxy, amino optionally mono- or di-substitutedwith C₁₋₆ alkyl, amido, or (lower alkyl)amide; (ii) C₃₋₇ cycloalkyl,C₃₋₇ cycloalkoxy, or C₄₋₁₀ alkylcycloalkyl, all optionally substitutedwith hydroxy, carboxyl, (C₁₋₆ alkoxy)carbonyl, amino optionally mono- ordi-substituted with C₁₋₆ alkyl, amido, or (lower alkyl) amide; (iii)amino optionally mono- or di-substituted with C₁₋₆ alkyl; amido; or(lower alkyl)amide; (iv) C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl, all optionallysubstituted with C₁₋₆ alkyl, hydroxy, amido, (lower alkyl)amide, oramino optionally mono- or di-substituted with C₁₋₆ alkyl; or (v) Het or(lower alkyl)-Het, both optionally substituted with C₁₋₆ alkyl, hydroxy,amido, (lower alkyl) amide, or amino optionally mono- or di-substitutedwith C₁₋₆ alkyl; R₅ is H or C₁₋₆ alkyl; with the proviso that when R₄ isan amide or a thioamide, R₄ is not (ii) a cycloalkoxy; Y is H or C₁₋₆alkyl; R₃ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, or C₄₋₁₀ alkylcycloalkyl, alloptionally substituted with hydroxy, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, amido,(lower alkyl)amido, C₆ or C₁₀ aryl, or C₇₋₁₆ aralkyl; R₂ is CH₂—R₂₀,NH—R₂₀, O—R₂₀ or S—R₂₀, wherein R₂₀ is a saturated or unsaturated C₃₋₇cycloalkyl or C₄₋₁₀ (alkylcycloalkyl), all of which being optionallymono-, di- or tri-substituted with R₂₁, or R₂₀ is a C₆ or C₁₀ aryl orC₇₋₁₄ aralkyl, all optionally mono-, di- or tri-substituted with R₂₁, orR₂₀ is Het or (lower alkyl)-Het, both optionally mono-, di- ortri-substituted with R₂₁, wherein each R₂₁ is independently C₁₋₆ alkyl;C₁₋₆ alkoxy; lower thioalkyl; sulfonyl; N0₂; OH; SH; halo; haloalkyl;amino optionally mono- or di-substituted with C₁₋₆ alkyl, C₆ or C₁₀aryl, C₇₋₁₄ aralkyl, Het or (lower alkyl)-Het; amido optionallymono-substituted with C₁₋₆ alkyl, C₆ or C₁₀ aryl, C₇₋₁₄ aralkyl, Het or(lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C₆ or C₁₀ aryl, C₇₋₁₄aralkyl or Het, said aryl, aralkyl or Het being optionally substitutedwith R₂₂; wherein R₂₂ is C₁₋₆ alkyl; C₃₋₇ cycloalkyl; C₁₋₆ alkoxy; aminooptionally mono- or di-substituted with C₁₋₆ alkyl; sulfonyl; (loweralkyl)sulfonyl; N0₂; OH; SH; halo; haloalkyl; carboxyl; amide; (loweralkyl)amide; or Het optionally substituted with C₁₋₆ alkyl; R1 is H;C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, alloptionally substituted with halogen. w. Formula XXII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinW is CH or N, R²¹ is H, halo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, hydroxy, or N(R²³)₂, whereineach R²³ is independently H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; R²² is H,halo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ thioalkyl, C₁₋₆alkoxy, C₃₋₆ cycloalkoxy, C₂₋₇ alkoxyalkyl, C₃₋₆ cycloalkyl, C_(6 or 10)aryl or Het, wherein Het is a five-, six-, or seven-membered saturatedor unsaturated heterocycle containing from one to four heteroatomsselected from nitrogen, oxygen and sulfur; said cycloalkyl, aryl or Hetbeing substituted with R²⁴, wherein R²⁴ is H, halo, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, NO₂, N(R²⁵)₂, NH—C(O)—R²⁵ orNH—C(O)—NH—R²⁵, wherein each R²⁵ is independently: H, C₁₋₆ alkyl or C₃₋₆cycloalkyl; or R²⁴ is NH—C(O)—OR²⁶ wherein R²⁶ is C₁₋₆ alkyl or C₃₋₆cycloalkyl; R³ is hydroxy, NH₂, or a group of formula —NH—R³¹, whereinR³¹ is C_(6 or 10) aryl, heteroaryl, —C(O)—R³², —C(O)—NHR³² or—C(O)—OR³², wherein R³² is C₁₋₆ alkyl or C₃₋₆ cycloalkyl; D is a 5 to10-atom saturated or unsaturated alkylene chain optionally containingone to three heteroatoms independently selected from: O, S, or N—R⁴¹,wherein R⁴¹ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or —C(O)—R⁴², wherein R⁴²is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or C_(6 or 10) aryl; R⁴ is H or from oneto three substituents at any carbon atom of said chain D, saidsubstituent independently selected from the group consisting of: C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, hydroxy, halo, amino, oxo, thio andC₁₋₆ thioalkyl, and A is an amide of formula —C(O)—NH—R⁵, wherein R⁵ isselected from the group consisting of: C₁₋₈ alkyl, C₃₋₆ cycloalkyl,C_(6 or 10) aryl and C₇₋₁₆ aralkyl; or A is a carboxylic acid. x.Formula XXIII:

a pharmaceutically acceptable salt, solvate or ester thereof; wherein inFormula XXIII above: R⁰ is a bond or difluoromethylene; R¹ is hydrogen;R² and R⁹ are each independently optionally substituted aliphatic group,optionally substituted cyclic group or optionally substituted aromaticgroup; R3, R5 and R7 are each independently: optionally substituted(1,1- or 1,2-)cycloalkylene; or optionally substituted (1,1- or1,2-)heterocyclylene; or methylene or ethylene), substituted with onesubstituent selected from the group consisting of an optionallysubstituted aliphatic group, an optionally substituted cyclic group oran optionally substituted aromatic group, and wherein the methylene orethylene is further optionally substituted with an aliphatic groupsubstituent; or; R4, R6, R8 and R¹⁰ are each independently hydrogen oroptionally substituted aliphatic group;

is substituted monocyclic azaheterocyclyl or optionally substitutedmulticyclic azaheterocyclyl, or optionally substituted multicyclicazaheterocyclenyl wherein the unsaturatation is in the ring distal tothe ring bearing the R⁹-L-(N(R⁸)—R⁷—C(O)—)_(n)N(R⁶)—R⁵—C(O)—N moiety andto which the —C(O)—N(R⁴)—R³—C(O)C(O)NR²R¹ moiety is attached; L is—C(O)—, —OC(O)—, —NR¹⁰C(O)—, —S(0)₂—, or —NR¹⁰S(0)₂—; and n is 0 or 1,provided when

is substituted

then L is —OC(O)— and R⁹ is optionally substituted aliphatic; or atleast one of R³, R⁵ and R⁷ is ethylene, substituted with one substituentselected from the group consisting of an optionally substitutedaliphatic group, an optionally substituted cyclic group or an optionallysubstituted aromatic group and wherein the ethylene is furtheroptionally substituted with an aliphatic group substituent; or R⁴ isoptionally substituted aliphatic; y. Formula XXIV:

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XXIV above: W is:

m is 0 or 1; R² is independently hydrogen, alkyl, alkenyl, aryl,aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl,heteroaryl, or heteroaralkyl, wherein any R² carbon atom is optionallysubstituted with J; J is alkyl, aryl, aralkyl, alkoxy, aryloxy,aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy,heterocyclylalkyl, keto, hydroxy, amino, alkylamino, alkanoylamino,aroylamino, aralkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl,halo, cyano, nitro, formyl, acyl, sulfonyl, or sulfonamido and isoptionally substituted with 1-3 J¹ groups; J¹ is alkyl, aryl, aralkyl,alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, amino,alkanoylamino, aroylamino, carboxy, carboxyalkyl, carboxamidoalkyl,halo, cyano, nitro, formyl, sulfonyl, or sulfonamido; L is alkyl,alkenyl, or alkynyl, wherein any hydrogen is optionally substituted withhalogen, and wherein any hydrogen or halogen atom bound to any terminalcarbon atom is optionally substituted with sulfhydryl or hydroxy; A¹ isa bond; R⁴ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, orcarboxamidoalkyl, and is optionally substituted with 1-3 J groups; R⁵and R⁶ are independently hydrogen, alkyl, alkenyl, aryl, aralkyl,aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionallysubstituted with 1-3 J groups; X is a bond, —C(H)(R7)-, -0-, —S—, or—N(R8)-; R⁷ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionallysubstititued with 1-3 J groups; R⁸ is hydrogen alkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, aralkanoyl,heterocyclanoyl, heteroaralkanoyl, —C(O)R¹⁴, —S0₂R¹⁴, or carboxamido,and is optionally substititued with 1-3 J groups; or R⁸ and Z, togetherwith the atoms to which they are bound, form a nitrogen containing mono-or bicyclic ring system optionally substituted with 1-3 J groups; R¹⁴ isalkyl, aryl, aralkyl, heterocyclyl, heterocyclyalkyl, heteroaryl, orheteroaralkyl; Y is a bond, —CH₂—, —C(O)—, —C(O)C(O)—, —S(O)—, —S(0)₂—,or —S(O)(NR⁷)—, wherein R⁷ is as defined above; Z is alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, —OR², or —N(R²)₂, wherein any carbon atom isoptionally substituted with J, wherein R² is as defined above; A² is abond or

R⁹ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and isoptionally substituted with 1-3 J groups; M is alkyl, cycloalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl,optionally substituted by 1-3 J groups, wherein any alkyl carbon atommay be replaced by a heteroatom; V is a bond, —CH₂—, —C(H)(R¹¹)—, -0-,—S—, or —N(R¹¹)—; R¹¹ is hydrogen or C₁₋₃ alkyl; K is a bond, -0-, —S—,—C(O)—, —S(O)—, —S(0)₂—, or —S(O)(NR¹¹)—, wherein R¹¹ is as definedabove; T is —R¹², -alkyl-R¹², -alkenyl-R¹², -alkynyl-R¹², —OR¹²,—N(R¹²)₂, —C(O)R¹², —C(═NOalkyl)R¹², or

R¹² is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl,cycloalkylidenyl, or heterocycloalkylidenyl, and is optionallysubstituted with 1-3 J groups, or a first R¹² and a second R¹², togetherwith the nitrogen to which they are bound, form a mono- or bicyclic ringsystem optionally substituted by 1-3 J groups; R¹⁰ is alkyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionallysubstituted with 1-3 hydrogens J groups; R¹⁵ is alkyl, cycloalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl,carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with1-3 J groups; and R¹⁶ is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl,or heterocyclyl; and z. z. Formula XXV

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinE represents CHO or B(OH)₂; R¹ represents lower alkyl, halo-lower alkyl,cyano-lower alkyl, lower alkylthio-lower alkyl, aryl-loweralkylthio-lower alkyl, aryl-lower alkyl, heteroaryllower alkyl, loweralkenyl or lower alkynyl; R² represents lower alkyl, hydroxy-loweralkyl, carboxylower alkyl, aryl-lower alkyl, aminocarbonyl-lower alkylor lower cycloalkyl-lower alkyl; and R³ represents hydrogen or loweralkyl; or R² and R³ together represent di- or trimethylene optionallysubstituted by hydroxy; R⁴ represents lower alkyl, hydroxy-lower alkyl,lower cycloalkyl-lower alkyl, carboxy-lower alkyl, aryllower alkyl,lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl,aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl or lowercycloalkyl; R⁵ represents lower alkyl, hydroxy-lower alkyl, loweralkylthio-lower alkyl, aryl-lower alkyl, aryl-lower alkylthio-loweralkyl, cyano-lower alkylthio-lower alkyl or lower cycloalkyl; R⁶represents hydrogen or lower alkyl; R⁷ represent lower alkyl,hydroxydower alkyl, carboxylower alkyl, aryl-iower alkyl, lowercycloalkyl-lower alkyl or lower cycloalkyl; R⁸ represents lower alkyl,hydroxy-lower alkyl, carboxylower alkyl or aryl-lower alkyl; and R⁹represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl,arylcarbonyl, lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonylor aryl-lower alkoxycarbonyl. z1. Formula XXVI:

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XXVI above B is an acyl derivative of formula R₁₁—C(O)—wherein R₁₁ is Cl-10 alkyl optionally substituted with carboxyl; or R₁₁is C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substituted with a C₁₋₆alkyl; a is 0 or 1; R₆, when present, is carboxy(lower)alkyl; b is 0 or1; R₅, when present, is C₁₋₆ alkyl, or carboxy(lower)alkyl; Y is H orC₁₋₆ alkyl; R₄ is C₁₋₁₀ alkyl; C₃₋₁₀ cycloalkyl; R₃ is C1-10 alkyl;C₃₋₁₀ cycloalkyl; W is a group of formula:

wherein R₂ is C₁₋₁₀ alkyl or C₃₋₇ cycloalkyl optionally substituted withcarboxyl; C₆ or C₁₀ aryl; or C₇₋₁₆ aralkyl; or W is a group of formula:

wherein X is CH or N; and R₂′ is C₃₋₄ alkylene that joins X to form a 5-or 6-membered ring, said ring optionally substituted with OH; SH; NH2;carboxyl; R₁₂; OR₁₂, SR₁₂, NHR₁₂ or NR₁₂R₁₂′ wherein R₁₂ and R₁₂′ areindependently: cyclic C₃₋₁₆ alkyl or acyclic C₁₋₁₆ alkyl or cyclic C₃₋₁₆alkenyl or acyclic C₂₋₁₆ alkenyl, said alkyl or alkenyl optionallysubstituted with NH₂, OH, SH, halo, or carboxyl; said alkyl or alkenyloptionally containing at least one heteroatom selected independentlyfrom the group consisting of: 0, S, and N; or R₁₂ and R₁₂′ areindependently C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substitutedwith C₁₋₆ alkyl, NH₂, OH, SH, halo, carboxyl or carboxy(lower)alkyl;said aryl or aralkyl optionally containing at least one heteroatomselected independently from the group consisting of: 0, S, and N; saidcyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fusedwith a second 5-, 6-, or 7-membered ring to form a cyclic system orheterocycle, said second ring being optionally substituted with NH₂. OH,SH, halo, carboxyl or carboxy(lower)alkyl; C₆ or C₁₀ aryl, orheterocycle; said second ring optionally containing at least oneheteroatom selected independently from the group consisting of: 0, S,and N; Q is a group of the formula:

wherein Z is CH; X is 0 or S; R₁ is H, C₁₋₆ alkyl or C₁₋₆ alkenyl bothoptionally substituted with thio or halo; and R₁₃ is C0-NH—R₁₄ whereinR₁₄ is hydrogen, cyclic C₃₋₁₀ alkyl or acyclic C₁₋₁₀ alkyl or cyclicC₃₋₁₀ alkenyl or acyclic C₂₋₁₀ alkenyl, said alkyl or alkenyl optionallysubstituted with NH₂, OH, SH, halo or carboxyl; said alkyl or alkenyloptionally containing at least one heteroatom selected independentlyfrom the group consisting of: 0, S, and N; or R₁₄ is C₆ or C₁₀ aryl orC₇₋₁₆ aralkyl optionally substituted with C₁₋₆ alkyl, NH₂, OH, SH, halo,carboxyl or carboxy(lower)alkyl or substituted with a further C₃₋₇cycloalkyl, C₆ or C₁₀ aryl, or heterocycle; said aryl or aralkyloptionally containing at least one heteroatom selected independentlyfrom the group consisting of: 0, S, and N; said cyclic alkyl, cyclicalkenyl, aryl or aralkyl being optionally fused with a second 5-, 6-, or7-membered ring to form a cyclic system or heterocycle, said second ringbeing optionally substituted with NH₂, OH, SH, halo, carboxyl orcarboxy(lower)alkyl or substituted with a further C₃₋₇ cycloalkyl, C₆ orC₁₀ aryl, or heterocycle; said second ring optionally containing atleast one heteroatom selected independently from the group consistingof: 0, S, and N; with the proviso that when Z is CH, then R₁₃ is not anα-amino acid or an ester thereof; Q is a phosphonate group of theformula:

wherein R₁₅ and R₁₆ are independently C₆₋₂₀ aryloxy; and R₁ is asdefined above.
 2. A method of increasing bioavailability of a compoundof Formulae I-XXVI in a subject comprising administering the at leastone compound of Formulae I-XXVI in combination with food compared toadministration of the at least one compound of Formulae I-XXVI withoutfood, wherein the at least one compound is selected from the groupconsisting of compounds of Formulae I to XXVI below: a. Formula I

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinin Formula I above: Y is selected from the group consisting of thefollowing moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy,aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe optionallysubstituted with X¹¹ or X¹²; X¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with theproviso that X¹¹ may be additionally optionally substituted with X¹²;X¹² is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²; R¹is COR⁵, wherein R⁵ is COR⁷ wherein R⁷ is NHR⁹, wherein R⁹ is selectedfrom the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl,cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl,[CH(R^(1′))]_(p)COOR¹¹, [CH(R^(1′))]_(p)CONR¹²R¹³,[CH(R^(1′))]_(p)SO₂R¹¹, [CH(R^(1′))]_(p)COR¹¹,[CH(R^(1′))]_(p)CH(OH)R¹¹, CH(R^(1′))CONHCH(R²)COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONR¹²R¹³,CH(R^(1′))CONHCH(R²)R′,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))COOR¹¹andCH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))CONR¹²R¹³,wherein R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), R¹¹, R¹², R¹³, and R′are independently selected from the group consisting of H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl,aryl-alkyl and heteroaralkyl; Z is selected from O, N, CH or CR; W maybepresent or absent, and if W is present, W is selected from C═O, C═S,C(═N—CN), or SO₂; Q maybe present or absent, and when Q is present, Q isCH, N, P, (CH₂)_(p), (CHR)_(p), (CRR′)_(p), O, NR, S, or SO₂; and when Qis absent, M may be present or absent; when Q and M are absent, A isdirectly linked to L; A is O, CH₂, (CHR)_(p), (CHR—CHR′)_(p),(CRR′)_(p), NR, S, SO₂ or a bond; E is CH, N, CR, or a double bondtowards A, L or G; G may be present or absent, and when G is present, Gis (CH₂)_(p), (CHR)_(p), or (CRR′)_(p); and when G is absent, J ispresent and E is directly connected to the carbon atom in Formula I as Gis linked to; J may be present or absent, and when J is present, J is(CH₂)_(p), (CHR)_(p), or (CRR′)_(p), SO₂, NH, NR or O; and when J isabsent, G is present and E is directly linked to N shown in Formula I aslinked to J; L may be present or absent, and when L is present, L is CH,CR, O, S or NR; and when L is absent, then M may be present or absent;and if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; M may be present or absent, and when M is present, M is O, NR, S,SO₂, (CH₂)_(p), (CHR)_(p)(CHR—CHR′)_(p), or (CRR′)_(p); p is a numberfrom 0 to 6; and R, R′, R², R³ and R⁴ are independently selected fromthe group consisting of H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₃-C₈cycloalkyl; C₃-C₈ heterocycloalkyl, alkoxy, aryloxy, alkylthio,arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone,aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms; aryl;heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl,heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl moieties may be optionally and chemically-suitablysubstituted, with said term “substituted” referring to optional andchemically-suitable substitution with one or more moieties selected fromthe group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl,cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy,alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate,urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone,sulfonyl urea, hydrazide, and hydroxamate; further wherein said unitN—C-G-E-L-J-N represents a five-membered or six-membered cyclic ringstructure with the proviso that when said unit N—C-G-E-L-J-N representsa five-membered cyclic ring structure, or when the bicyclic ringstructure in Formula I comprising N, C, G, E, L, J, N, A, Q, and Mrepresents a five-membered cyclic ring structure, then saidfive-membered cyclic ring structure lacks a carbonyl group as part ofthe cyclic ring; b. Formula II

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula II above: Z is NH; X is alkylsulfonyl, heterocyclylsulfonyl,heterocyclylalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,alkyaminocarbonyl, heterocyclylaminocarbonyl, arylaminocarbonyl, orheteroarylaminocarbonyl moiety, with the proviso that X may beadditionally optionally substituted with R¹² or R¹³; X¹ is H; C₁-C₄straight chain alkyl; C₁-C₄ branched alkyl or; CH₂-aryl (substituted orunsubstituted); R¹² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl moiety, withthe proviso that R¹² may be additionally optionally substituted withR¹³. R¹³ is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitromoiety, with the proviso that the alkyl, alkoxy, and aryl may beadditionally optionally substituted with moieties independently selectedfrom R¹³. P1a, P1b, P2, P3, P4, P5, and P6 are independently: H; C1-C10straight or branched chain alkyl; C2-C10 straight or branched chainalkenyl; C3-C8 cycloalkyl, C3-C8 heterocyclic; (cycloalkyl)alkyl or(heterocyclyl)alkyl, wherein said cycloalkyl is made up of 3 to 8 carbonatoms, and zero to 6 oxygen, nitrogen, sulfur, or phosphorus atoms, andsaid alkyl is of 1 to 6 carbon atoms; aryl, heteroaryl, arylalkyl, orheteroarylalkyl, wherein said alkyl is of 1 to 6 carbon atoms; whereinsaid alkyl, alkenyl, cycloalkyl, heterocyclyl; (cycloalkyl)alkyl and(heterocyclyl)alkyl moieties may be optionally substituted with R¹³, andfurther wherein said P1a and P1b may optionally be joined to each otherto form a spirocyclic or spiroheterocyclic ring, with said spirocyclicor spiroheterocyclic ring containing zero to six oxygen, nitrogen,sulfur, or phosphorus atoms, and may be additionally optionallysubstituted with R¹³; and P1′ is H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclyl-alkyl, aryl, aryl-alkyl,heteroaryl, or heteroaryl-alkyl; with the proviso that said P1′ may beadditionally optionally substituted with R¹³; c. Formula III

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula III above: G is carbonyl; J and Y may be the same ordifferent and are independently selected from the group consisting ofthe moieties: H, alkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy,aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe additionallyoptionally substituted with X¹¹ or X¹²; X¹¹ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl moiety, with the proviso that X¹¹may be additionally optionally substituted with X¹²; X¹² is hydroxy,alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino,arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²; R¹is COR⁵ or B(OR)₂, wherein R⁵ is selected from the group consisting ofH, OH, OR⁸, NR⁹R¹⁰, CF₃, C₂F₅, C₃F₇, CF₂R⁶, R⁶ and COR⁷ wherein R⁷ isselected from the group consisting of H, OH, OR⁸, CHR⁹R¹⁰, and NR⁹R¹⁰,wherein R⁶, R⁸, R⁹ and R¹⁰ may be the same or different and areindependently selected from the group consisting of H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl,heteroarylalkyl, CH(R^(1,))COOR¹¹, CH(R^(1,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))COOR¹¹, CH(R^(1′))CONHCH(R^(2,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))R′,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))COOR¹¹,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))COOR¹¹,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))CONHCH(R^(5,))COOR¹¹,andCH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))CONHCH(R^(5,))CONR¹²R¹³,wherein R^(1,),R^(2,),R^(3,),R^(4,),R^(5,),R¹¹,R¹²,R¹³, and R′ may bethe same or different and are independently selected from a groupconsisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl,alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; Z isselected from O, N, or CH; W maybe present or absent, and if W ispresent, W is selected from C═O, C═S, or SO₂; and R, R′, R², R³ and R⁴are independently selected from the group consisting of H; C1-C10 alkyl;C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro; oxygen, nitrogen,sulfur, or phosphorus atoms (with said oxygen, nitrogen, sulfur, orphosphorus atoms numbering zero to six); (cycloalkyl)alkyl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms; aryl;heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl,heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl moieties may be optionally substituted, with said term“substituted” referring to optional and chemically-suitable substitutionwith one or more moieties selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen,hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido,ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,sulfonamide, sulfoxide, sulfone, sulfonylurea, hydrazide, andhydroxamate; d. Formula IV

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: Y is selected from the group consisting of the followingmoieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe optionallysubstituted with X¹¹ or X¹²; X¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with theproviso that X¹¹ may be additionally optionally substituted with X¹²;X¹² is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²; R¹is selected from the following structures:

wherein k is a number from 0 to 5, which can be the same or different,R¹¹ denotes optional substituents, with each of said substituents beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, cycloalkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino,heterocycloalkylamino, hydroxy, thio, alkylthio, arylthio, amino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido,carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, and nitro,with the proviso that R¹¹ (when R¹¹≠H) maybe optionally substituted withX¹¹ or X¹²; Z is selected from O, N, CH or CR; W may be present orabsent, and if W is present, W is selected from C═O, C═S, C(═N—CN), orS(O₂); Q may be present or absent, and when Q is present, Q is CH, N, P,(CH₂)_(p), (CHR)_(p), (CRR′)_(p), O, N(R), S, or S(O₂); and when Q isabsent, M may be present or absent; when Q and M are absent, A isdirectly linked to L; A is O, CH₂, (CHR)_(p), (CHR—CHR′)_(p),(CRR′)_(p), N(R), S, S(O₂) or a bond; E is CH, N, CR, or a double bondtowards A, L or G; G may be present or absent, and when G is present, Gis (CH₂)_(p), (CHR)_(p), or (CRR′)_(p); and when G is absent, J ispresent and E is directly connected to the carbon atom in Formula I as Gis linked to; J may be present or absent, and when J is present, J is(CH₂)_(p), (CHR)_(p), or (CRR′)_(p), S(O₂), NH, N(R) or O; and when J isabsent, G is present and E is directly linked to N shown in Formula I aslinked to J; L may be present or absent, and when L is present, L is CH,C(R), O, S or N(R); and when L is absent, then M may be present orabsent; and if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; M may be present or absent, and when M is present, M is O, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p)(CHR—CHR′)_(p), or (CRR′)_(p); p is a numberfrom 0 to 6; and R, R′, R², R³ and R⁴ can be the same or different, eachbeing independently selected from the group consisting of H; C₁-C₁₀alkyl; C₂-C₁₀ alkenyl; C₃-C₈ cycloalkyl; C₃-C₈ heterocycloalkyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro, halogen,(cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkylis made of three to eight carbon atoms, and zero to six oxygen,nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to sixcarbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionallysubstituted, with said term “substituted” referring to substitution withone or more moieties which can be the same or different, each beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy,thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester,carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, andhydroxamate; further wherein said unit N—C-G-E-L-J-N represents afive-membered cyclic ring structure or six-membered cyclic ringstructure with the proviso that when said unit N—C-G-E-L-J-N representsa five-membered cyclic ring structure, or when the bicyclic ringstructure in Formula I comprising N, C, G, E, L, J, N, A, Q, and Mrepresents a five-membered cyclic ring structure, then saidfive-membered cyclic ring structure lacks a carbonyl group as part ofsaid five-membered cyclic ring. e) Formula V

or a pharmaceutically acceptable salt, solvate or ester of said compoundwherein: (1) R¹ is —C(O)R⁵ or —B(OR)₂; (2) R⁵ is H, —OH, —OR⁸, —NR⁹R¹⁰,—C(O)OR⁸, —C(O)NR⁹R¹⁰, —CF₃, —C₂F₅, C₃F₇, —CF₂R⁶, —R⁶, —C(O)R⁷ orNR⁷SO₂R⁸; (3) R⁷ is H, —OH, —OR⁸, or —CHR⁹R¹⁰; (4) R⁶, R⁸, R⁹ and R¹⁰are independently selected from the group consisting of H: alkyl,alkenyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl,heteroarylalkyl, R¹⁴, —CH(R^(1′))CH(R^(1′))C(O)OR¹¹,[CH(R^(1′))]_(p)C(O)OR¹¹, —[CH(R^(1′))]_(p)C(O)NR¹²R¹³,—[CH(R^(1′))]_(p)S(O₂)R¹¹, —[CH(R^(1′))]_(p)C(O)R¹¹,—[CH(R^(1′))]_(p)S(O₂)NR¹²R¹³, CH(R^(1′))C(O)N(H)CH(R^(2′))(R′),CH(R^(1′))CH(R^(1′))C(O)NR¹²R¹³, —CH(R^(1′))CH(R^(1′))S(O₂)R¹¹,—CH(R^(1′))CH(R^(1′))S(O₂)NR¹²R¹³, —CH(R^(1′))CH(R^(1′))C(O)R¹¹,—[CH(R^(1′))]_(p)CH(OH)R¹¹, —CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)OR¹¹,C(O)N(H)CH(R^(2′))C(O)OR¹¹, —C(O)N(H)CH(R^(2′))C(O)R¹¹,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)NR¹²R¹³,—CH(R^(1′))C(O)N(H)CH(R^(2′))R′,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)OR¹¹,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)CH(R^(3′))NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)OR¹¹,H(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)N(H)CH(R^(5′))C(O)OR¹¹,andCH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)N(H)CH(R^(5′))C(O)NR¹²R¹³;wherein R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), R¹¹, R¹² and R¹³ can bethe same or different, each being independently selected from the groupconsisting of: H, halogen, alkyl, aryl, heteroalkyl, heteroaryl,cycloalkyl, alkoxy, aryloxy, alkenyl, alkynyl, alkyl-aryl,alkyl-heteroaryl, heterocycloalkyl, aryl-alkyl and heteroaralkyl; or R¹²and R¹³ are linked together wherein the combination is cycloalkyl,heterocycloalkyl, ary or heteroaryl; R¹⁴ is present or not and ifpresent is selected from the group consisting of: H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, allyl,alkyl-heteroaryl, alkoxy, aryl-alkyl, alkenyl, alkynyl andheteroaralkyl; (5) R and R′ are present or not and if present can be thesame or different, each being independently selected from the groupconsisting of: H, OH, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₃-C₈ cycloalkyl,C₃-C₈ heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio,alkylamino, arylamino, amino, amido, arylthioamino, arylcarbonylamino,arylaminocarboxy, alkylaminocarboxy, heteroalkyl, alkenyl, alkynyl,(aryl)alkyl, heteroarylalkyl, ester, carboxylic acid, carbamate, urea,ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl, aryl,heteroaryl, (alkyl)aryl, alkylheteroaryl, alkyl-heteroaryl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms; (6) L′is H, OH, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, orheterocyclyl; (7) M′ is H, alkyl, heteroalkyl, aryl, heteroaryl,cycloalkyl, arylalkyl, heterocyclyl or an amino acid side chain; or L′and M′ are linked together to form a ring structure wherein the portionof structural Formula 1 represented by

is represented by structural Formula 2:

wherein in Formula 2: E is present or absent and if present is C, CH, Nor C(R); J is present or absent, and when J is present, J is (CH₂)_(p),(CHR—CHR′)_(p), (CHR)_(p), (CRR′)_(p), S(O₂), N(H), N(R) or O; when J isabsent and G is present, L is directly linked to the nitrogen atommarked position 2; p is a number from 0 to 6; L is present or absent,and when L is present, L is C(H) or C(R); when L is absent, M is presentor absent; if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; G is present or absent, and when G is present, G is (CH₂)_(p),(CHR)_(p), (CHR—CHR′)_(p) or (CRR′)_(p); when G is absent, J is presentand E is directly connected to the carbon atom marked position 1; Q ispresent or absent, and when Q is present, Q is NR, PR, (CR═CR),(CH₂)_(p), (CHR)_(p), (CRR′)_(p), (CHR—CHR′)_(p), O, NR, S, SO, or SO₂;when Q is absent, M is (i) either directly linked to A or (ii) anindependent substituent on L, said independent substituent bing selectedfrom —OR, —CH(R)(R′), S(O)₀₋₂R or —NRR′ or (iii) absent; when both Q andM are absent, A is either directly linked to L, or A is an independentsubstituent on E, said independent substituent bing selected from —OR,—CH(R)(R′), S(O)₀₋₂R or —NRR′ or A is absent; A is present or absent andif present A is O, O(R), (CH₂)_(p), (CHR)_(p), (CHR—CHR′)_(p),(CRR′)_(p), N(R), NRR′, S, S(O₂), —OR, CH(R)(R′) or NRR′; or A is linkedto M to form an alicyclic, aliphatic or heteroalicyclic bridge; M ispresent or absent, and when M is present, M is halogen, O, OR, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p) (CHR—CHR′)_(p), or (CRR′)_(p); or M islinked to A to form an alicyclic, aliphatic or heteroalicyclic bridge;(8) Z′ is represented by the structural Formula 3:

wherein in Formula 3, Y is selected from the group consisting of: H,aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, heteroalkyl-heteroaryl,heteroalkyl-heterocycloalkyl, cycloalkyloxy, alkylamino, arylamino,alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino andheterocycloalkylamino, and Y is unsubstituted or optionally substitutedwith one or two substituents which are the same or different and areindependently selected from X¹¹ or X¹²; X¹¹ is alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl,alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl,and X¹¹ is unsubstituted or optionally substituted with one or more ofX¹² moieties which are the same or different and are independentlyselected; X¹² is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl,aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,carbalkoxy, carboxamido, alkylcarbonyl, arylcarbonyl,heteroalkylcarbonyl, heteroarylcarbonyl, sulfonylurea,cycloalkylsulfonamido, heteroaryl-cycloalkylsulfonamido,heteroaryl-sulfonamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halogen, cyano, or nitro, and said alkyl,alkoxy, and aryl are unsubstituted or optionally independentlysubstituted with one or more moieties which are the same or differentand are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl; Z is O, N,C(H) or C(R); R³¹ is H, hydroxyl, aryl, alkyl, alkyl-aryl, heteroalkyl,heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy,alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy,heteroalkyl-heteroaryl, cycloalkyloxy, alkylamino, arylamino,alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino orheterocycloalkylamino, and R³¹ is unsubstituted or optionallysubstituted with one or two substituents which are the same or differentand are independently selected from X¹³ or X¹⁴; X¹³ is alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl,aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, orheteroarylalkyl, and X¹³ is unsubstituted or optionally substituted withone or more of X¹⁴ moieties which are the same or different and areindependently selected; X¹⁴ is hydroxy, alkoxy, alkyl, alkenyl, alkynyl,aryl, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,carbalkoxy, carboxamido, alkylcarbonyl, arylcarbonyl,heteroalkylcarbonyl, heteroarylcarbonyl, cycloalkylsulfonamido,heteroaryl-cycloalkylsulfonamido, heteroarylsulfonamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,halogen, cyano, or nitro, and said alkyl, alkoxy, and aryl areunsubstiuted or optionally independently substituted with one or moremoieties which are the same or different and are independently selectedfrom alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl; W may be present or absent, and ifW is present, W is C(═O), C(═S), C(═N—CN), or S(O₂); (9) X isrepresented by structural Formula 4:

wherein in Formula 4, a is 2, 3, 4, 5, 6, 7, 8 or 9; b, c, d, e and fare0, 1, 2, 3, 4 or 5; A is C, N, S or O; R²⁹ and R^(29′) are independentlypresent or absent and if present can be the same or different, eachbeing independently one or two substituents independently selected fromthe group consisting of: H, halo, alkyl, aryl, cycloalkyl,cycloalkylamino, cycloalkylaminocarbonyl, cyano, hydroxy, alkoxy,alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxyl,C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl,alkylheteroaryl, heteroaralkenyl, hydroxyalkyl, aryloxy, aralkoxy, acyl,aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkenyl, heterocyclyl, heterocyclenyl,Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ can be thesame or different and are independently selected from the groupconsisting of hydrogen, alkyl, aryl, and aralkyl; or R²⁹ and R^(29′) arelinked together such that the combination is an aliphatic orheteroaliphatic chain of 0 to 6 carbons; R³⁰ is present or absent and ifpresent is one or two substituents independently selected from the groupconsisting of: H, alkyl, aryl, heteroaryl and cylcoalkyl; (10) D isrepresented by structural Formula 5:

wherein in Formula 5, R³², R³³ and R³⁴ are present or absent and ifpresent are independently one or two substituents independently selectedfrom the group consisting of: H, halo, alkyl, aryl, cycloalkyl,cycloalkylamino, spiroalkyl, cycloalkylaminocarbonyl, cyano, hydroxy,alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂,carboxyl, —C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl, aralkenyl,heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxyalkyl, aryloxy,aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl,arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkenyl, heterocyclyl, heterocyclenyl,Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ can be thesame or different and are independently selected from the groupconsisting of hydrogen, alkyl, aryl, and aralkyl; or R³² and R³⁴ arelinked together such that the combination forms a portion of acycloalkyl group; g is 1, 2, 3, 4, 5, 6, 7, 8 or 9; h, i, j, k, l and mare 0, 1, 2, 3, 4 or 5; and A is C, N, S or O, (11) provided that whenstructural Formula 2:

W′ is CH or N, both the following conditional exclusions (i) and (ii)apply: conditional exclusion (i): Z′ is not —NH—R³⁶, wherein R³⁶ is H,C_(6 or 10) aryl, heteroaryl, —C(O)—R³⁷, —C(O)—OR³⁷ or —C(O)—NHR³⁷,wherein R³⁷ is C₁₋₆alkyl or C cycloalkyl; and conditional exclusion(ii): R¹ is not —C(O)OH, a pharmaceutically acceptable salt of —C(O)OH,an ester of —C(O)OH or —C(O)NHR³⁸ wherein R³⁸ is selected from the groupconsisting of C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C_(6 to 10) aryl or C₇₋₁₆aralkyl. f. Formula VI

or a pharmaceutically acceptable salt, solvate or ester of saidcompound, wherein in Formula VI above: Cap is H, alkyl, alkyl-aryl,heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl,alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy,cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy orheterocyclylamino, wherein each of said alkyl, alkyl-aryl, heteroalkyl,heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy,alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy,amino, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy orheterocyclylamino can be unsubstituted or optionally independentlysubstituted with one or two substituents which can be the same ordifferent and are independently selected from X¹ and X²; P′ is —NHR; X¹is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl,heteroaryl, heterocyclylamino, alkylheteroaryl, or heteroarylalkyl, andX¹ can be unsubstituted or optionally independently substituted with oneor more of X² moieties which can be the same or different and areindependently selected; X² is hydroxy, alkyl, aryl, alkoxy, aryloxy,thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halogen, cyano, keto, ester or nitro, wherein each of saidalkyl, alkoxy, and aryl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same or differentand are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino,alkylheteroaryl and heteroarylalkyl; W may be present or absent, andwhen W is present W is C(═O), C(═S), C(═NH), C(═N—OH), C(═N—CN), S(O) orS(O₂); Q maybe present or absent, and when Q is present, Q is N(R),P(R), CR═CR′, (CH₂)_(p), (CHR)_(p), (CRR′)_(p), (CHR—CHR′)_(p), O, S,S(O) or S(O₂); when Q is absent, M is (i) either directly linked to A or(ii) M is an independent substituent on L and A is an independentsubstituent on E, with said independent substituent being selected from—OR, —CH(R′), S(O)₀₋₂R or —NRR′; when both Q and M are absent, A iseither directly linked to L, or A is an independent substituent on E,selected from —OR, CH(R)(R′), —S(O)₀₋₂R or —NRR′; A is present or absentand if present A is —O—, —O(R)CH₂—, —(CHR)_(p)—, —(CHR—CHR′)_(p)—,(CRR′)_(p), N(R), NRR′, S, or S(O₂), and when Q is absent, A is —OR,—CH(R)(R′) or —NRR′; and when A is absent, either Q and E are connectedby a bond or Q is an independent substituent on M; E is present orabsent and if present E is CH, N, C(R); G may be present or absent, andwhen G is present, G is (CH₂)_(p), (CHR)_(p), or (CRR′)_(p); when G isabsent, J is present and E is directly connected to the carbon atommarked position 1; J may be present or absent, and when J is present, Jis (CH₂)_(p), (CHR—CHR′)_(p), (CHR)_(p), (CRR′)_(p), S(O₂), N(H), N(R)or O; when J is absent and G is present, L is directly linked to thenitrogen atom marked position 2; L may be present or absent, and when Lis present, L is CH, N, or CR; when L is absent, M is present or absent;if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; M may be present or absent, and when M is present, M is O, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p), (CHR—CHR′)_(p), or (CRR′)_(p); p is anumber from 0 to 6; R, R′ and R³ can be the same or different, eachbeing independently selected from the group consisting of: H, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, arylthioamino,arylcarbonylamino, arylaminocarboxy, alkylaminocarboxy, heteroalkyl,heteroalkenyl, alkenyl, alkynyl, aryl-alkyl, heteroarylalkyl, ester,carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,halogen, (cycloalkyl)alkyl, aryl, heteroaryl, alkyl-aryl,alkylheteroaryl, alkyl-heteroaryl and (heterocyclyl)alkyl; R and R′ in(CRR′) can be linked together such that the combination forms acycloalkyl or heterocyclyl moiety; and R¹ is carbonyl; g. Formula VII

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein, M is O, N(H), or CH₂; n is 0-4; R¹ is —OR⁶, —NR⁶R⁷ or

where R⁶ and R⁷ can be the same or different, each being independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino,arylamino and alkylamino; R⁴ and R⁵ can be the same or different, eachbeing independently selected from the group consisting of H, alkyl, aryland cycloalkyl; or alternatively R⁴ and R⁵ together form part of acyclic 5- to 7-membered ring such that the moiety

is represented by

where k is 0 to 2; X is selected from the group consisting of:

where p is 1 to 2, q is 1-3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and R³ is selected from the group consisting of: aryl,heterocyclyl, heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy. h. Formula VIII

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinin Formula VIII above, M is O, N(H), or CH₂; R¹ is —C(O)NHR⁶, where R⁶is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, hydroxyl, amino, arylamino oralkylamino; P₁ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl haloalkyl; P₃ is selected from the group consistingof alkyl, cycloalkyl, aryl and cycloalkyl fused with aryl; R⁴ and R⁵ canbe the same or different, each being independently selected from thegroup consisting of H, alkyl, aryl and cycloalkyl; or alternatively R⁴and R⁵ together form part of a cyclic 5- to 7-membered ring such thatthe moiety

is represented by

where k is 0 to 2; X is selected from the group consisting of:

where p is 1 to 2, q is 1 to 3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and R³ is selected from the group consisting of: aryl,heterocyclyl, heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy; i. formula IX:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein, M is O, N(H), or CH₂; n is 0-4; R¹ is —OR⁶, —NR⁶R⁷ or

where R⁶ and R⁷ can be the same or different, each being independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino,arylamino and alkylamino; R⁴ and R⁵ can be the same or different, eachbeing independently selected from the group consisting of H, alkyl, aryland cycloalkyl; or alternatively R⁴ and R⁵ together form part of acyclic 5- to 7-membered ring such that the moiety

is represented by

where k is 0 to 2; X is selected from the group consisting of:

where p is 1 to 2, q is 1 to 3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and R³ is selected from the group consisting of: aryl,heterocyclyl, heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy; j. Formula X

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula X above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, R¹⁵ and R¹⁶ are connected to eachother to form a four to eight-membered cycloalkyl, heteroaryl orheterocyclyl structure, and likewise, independently R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; k. Formula XI

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XI above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, NR⁹R¹⁰, SR, SO₂R, and halo; orA and M are connected to each other (in other words, A-E-L-M takentogether) such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NR⁹R¹⁰ forms afour to eight-membered heterocyclyl; Y is selected from the followingmoieties:

wherein Y³⁰ and Y³¹ are selected from

where u is a number 0-6; X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O)and SO₂; G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, T₃ and T₄can be the same or different, each being independently selected from thegroup consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl,alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl, or alternately, R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; l. Formula XII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XII above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, (i) either R¹⁵ and R¹⁶ areconnected to each other to form a four to eight-membered cyclicstructure, or R¹⁵ and R¹⁹ are connected to each other to form a four toeight-membered cyclic structure, and (ii) likewise, independently, R¹⁷and R¹⁸ are connected to each other to form a three to eight-memberedcycloalkyl or heterocyclyl; wherein each of said alkyl, aryl,heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of: □ulfonam, alkoxy, aryloxy, thio,alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, □ulfonamide, alkylsulfonamido, arylsulfonamido, alkyl,aryl, heteroaryl, keto, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo,cyano, and nitro; m. Formula XIII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XIII above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other (in other words, A-E-L-Mtaken together) such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O, and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ can be thesame or different, each being independently selected from the groupconsisting of H, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ heteroalkenyl, C₂-C₁₀ alkynyl, C₂-C₁₀ heteroalkynyl, C₃-C₈cycloalkyl, C₃-C₈ heterocyclyl, aryl, heteroaryl, or alternately: (i)either R¹⁵ and R¹⁶ can be connected to each other to form a four toeight-membered cycloalkyl or heterocyclyl, or R¹⁵ and R¹⁹ are connectedto each other to form a five to eight-membered cycloalkyl orheterocyclyl, or R¹⁵ and R²⁰ are connected to each other to form a fiveto eight-membered cycloalkyl or heterocyclyl, and (ii) likewise,independently, R¹⁷ and R¹⁸ are connected to each other to form a threeto eight-membered cycloalkyl or heterocyclyl, wherein each of saidalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstitutedor optionally independently substituted with one or more moietiesselected from the group consisting of: hydroxy, alkoxy, aryloxy, thio,alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, keto,carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro; n.Formula XIV

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XIV above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately R and R′ in NRR′ are connected toeach other such that NRR′ forms a four to eight-membered heterocyclyl;and Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, oralternately, (i) R¹⁵ and R¹⁶ are connected to each other to form a fourto eight-membered cyclic structure, and (ii) likewise, independently R¹⁷and R¹⁸ are connected to each other to form a three to eight-memberedcycloalkyl or heterocyclyl; wherein each of said alkyl, aryl,heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, alkyl,aryl, heteroaryl, keto, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo,cyano, and nitro; p. Formula XV

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XV above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, cycloalkyl-, arylalkyl-, orheteroarylalkyl; E and J can be the same or different, each beingindependently selected from the group consisting of R, OR, NHR, NRR⁷,SR, halo, and S(O₂)R, or E and J can be directly connected to each otherto form either a three to eight-membered cycloalkyl, or a three toeight-membered heterocyclyl moiety; Z is N(H), N═, or O, with theproviso that when Z is O, G is present or absent and if G is presentwith Z being O, then G is C(═O); G maybe present or absent, and if G ispresent, G is C(═O) or S(O₂), and when G is absent, Z is directlyconnected to Y; Y is selected from the group consisting of:

R, R⁷, R², R³, R⁴ and R⁵ can be the same or different, each beingindependently selected from the group consisting of H, alkyl-, alkenyl-,alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-, wherein each of said heteroalkyl, heteroaryl andheterocyclyl independently has one to six oxygen, nitrogen, sulfur, orphosphorus atoms; wherein each of said alkyl, heteroalkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl moieties can beunsubstituted or optionally independently substituted with one or moremoieties selected from the group consisting of alkyl, alkenyl, alkynyl,aryl, aralkyl, cycloalkyl, heterocyclyl, halo, hydroxy, thio, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide,sulfone, sulfonyl urea, hydrazide, and hydroxamate; q. Formula XVI

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XVI above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; R² and R³ can be the same or different,each being independently selected from the group consisting of H, alkyl,heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Y isselected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³,R²⁴ and R²⁵ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R¹⁷ andR¹⁸ are independently connected to each other to form a three toeight-membered cycloalkyl or heterocyclyl; (ii) likewise independentlyR¹⁵ and R¹⁹ are connected to each other to form a four to eight-memberedheterocyclyl; (iii) likewise independently R¹⁵ and R¹⁶ are connected toeach other to form a four to eight-membered heterocyclyl; (iv) likewiseindependently R¹⁵ and R²⁰ are connected to each other to form a four toeight-membered heterocyclyl; (v) likewise independently R²² and R²³ areconnected to each other to form a three to eight-membered cycloalkyl ora four to eight-membered heterocyclyl; and (vi) likewise independentlyR²⁴ and R²⁵ are connected to each other to form a three toeight-membered cycloalkyl or a four to eight-membered heterocyclyl;wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro; r. Formula XVII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XVII above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; Y is selected from the followingmoieties:

wherein Y³⁰ is selected from

where u is a number 0-1; X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O)and SO₂; G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, and T₃ canbe the same or different, each being independently selected from thegroup consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl,alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl, or alternately, R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; s. Formula XVIII:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein: R⁸ is selected from the group consisting of alkyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-,heteroarylalkyl-, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl and cycloalkyl; A and Mcan be the same or different, each being independently selected from R,OR, N(H)R, N(RR′), SR, S(O₂)R, and halo; or A and M are connected toeach other (in other words, A-E-L-M taken together) such that themoiety:

shown above in Formula I forms either a three, four, five, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC(R); L is C(H), C(R), CH₂C(R), or C(R)CH₂; R and R′ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in N(RR′) are connected to each other such that N(RR′) forms afour to eight-membered heterocyclyl; R² and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, spiro-linked cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl; Y is selected from thefollowing moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately (i) R¹⁷ and R¹⁸ are independentlyconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; (ii) likewise independently R¹⁵ and R¹⁹ are connected toeach other to form a four to eight-membered heterocyclyl; (iii) likewiseindependently R¹⁵ and R¹⁶ are connected to each other to form a four toeight-membered heterocyclyl; and (iv) likewise independently R¹⁵ and R²⁰are connected to each other to form a four to eight-memberedheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl,spiro-linked cycloalkyl, and heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, sulfonamido, alkyl, alkenyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro. t. Formula XIX

wherein in Formula XIX above: Z is selected from the group consisting ofa heterocyclyl moiety, N(H)(alkyl), —N(alkyl)₂, —N(H)(cycloalkyl),—N(cycloalkyl)₂, —N(H)(aryl, —N(aryl)₂, —N(H)(heterocyclyl),—N(heterocyclyl)₂, —N(H)(heteroaryl), and —N(heteroaryl)₂; R¹ is NHR⁹,wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-, heteroalkyl-,heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, or heteroarylalkyl;R² and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl; Y is selected from thefollowing moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ can bethe same or different, each being independently selected from the groupconsisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately (i) R¹⁷ and R¹⁸ are independentlyconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; (ii) likewise independently R¹⁵ and R¹⁹ are connected toeach other to form a four to eight-membered heterocyclyl; (iii) likewiseindependently R¹⁵ and R¹⁶ are connected to each other to form a four toeight-membered heterocyclyl; and (iv) likewise independently R¹⁵ and R²⁰are connected to each other to form a four to eight-memberedheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; u. Formula XX

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: a is 0 or 1; b is 0 or 1; Y is H or C₁₋₆ alkyl; B is H, an acylderivative of formula R₇—C(O)— or a sulfonyl of formula R₇—SO2 whereinR7 is (i) C_(l-10) alkyl optionally substituted with carboxyl, C₁₋₆alkanoyloxy or C₁₋₆ alkoxy; (ii) C₃₋₇ cycloalkyl optionally substitutedwith carboxyl, (C₁₋₆ alkoxy)carbonyl or phenylmethoxycarbonyl; (iii) C₆or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substituted with C₁₋₆ alkyl,hydroxy, or amino optionally substituted with C₁₋₆ alkyl; or (iv) Hetoptionally substituted with C₁₋₆ alkyl, hydroxy, amino optionallysubstituted with C₁₋₆ alkyl, or amido optionally substituted with C₁₋₆alkyl; R₆, when present, is C₁₋₆ alkyl substituted with carboxyl; R₅,when present, is C₁₋₆ alkyl optionally substituted with carboxyl; R₄ isC₁₋₁₀ alkyl, C₃₋₇ cycloalkyl or C₄₋₁₀ (alkylcycloalkyl); R₃ is C₁₋₁₀alkyl, C₃₋₇ cycloalkyl or C₄₋₁₀ (alkylcycloalkyl); R₂ is CH₂—R₂₀,NH—R₂₀, O—R₂₀ or S—R₂₀, wherein R₂₀ is a saturated or unsaturated C₃₋₇cycloalkyl or C₄₋₁₀ (alkyl cycloalkyl) being optionally mono-, di- ortri-substituted with R₂₁, or R₂₀ is a C₆ or C₁₀ aryl or C₇₋₁₆ aralkyloptionally mono-, di- or tri-substituted with R₂₁, or R₂₀ is Het or(lower alkyl)-Het optionally mono-, di- or tri-substituted with R₂₁,wherein each R₂₁ is independently C₁₋₆ alkyl; C₁₋₆alkoxy; aminooptionally mono- or di-substituted with C₁₋₆ alkyl; sulfonyl; N0₂; OH;SH; halo; haloalkyl; amido optionally mono-substituted with C₁₋₆ alkyl,C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl, Het or (lower alkyl)-Het; carboxyl;carboxy(lower alkyl); C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl or Het, said aryl,aralkyl or Het being optionally substituted with R₂₂; wherein R₂₂ isC₁₋₆alkyl; C₁₋₆ alkoxy; amino optionally mono- or di-substituted withC₁₋₆ alkyl; sulfonyl; N0₂; OH; SH; halo; haloalkyl; carboxyl; amide or(lower alkyl)amide; R₁ is C₁₋₆ alkyl or C₂₋₆ alkenyl optionallysubstituted with halogen; and W is hydroxy or a N-substituted amino. Inthe above-shown structure of the compound of Formula XX, the terms P6,P5, P4, P3, P2 and P1 denote the respective amino acid moieties as isconventionally known to those skilled in the art. v. Formula XXI

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: B is H, a C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl; Het or (loweralkyl)-Het, all of which optionally substituted with C₁₋₆ alkyl; C₁₋₆alkoxy; C₁₋₆ alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro;cyano; cyanoalkyl; amino optionally substituted with C₁₋₆ alkyl; amido;or (lower alkyl)amide; or B is an acyl derivative of formula R₄—C(O)—; acarboxyl of formula R₄-0-C(O)—; an amide of formula R₄—N(R₅)—C(O)—; athioamide of formula R₄—N(R₅)—C(S)—; or a sulfonyl of formula R₄—SO2wherein R₄ is (i) C₁₋₁₀ alkyl optionally substituted with carboxyl, C₁₋₆alkanoyl, hydroxy, C₁₋₆ alkoxy, amino optionally mono- or di-substitutedwith C₁₋₆ alkyl, amido, or (lower alkyl) amide; (ii) C₃₋₇ cycloalkyl,C₃₋₇ cycloalkoxy, or C₄₋₁₀ alkylcycloalkyl, all optionally substitutedwith hydroxy, carboxyl, (C₁₋₆ alkoxy)carbonyl, amino optionally mono- ordi-substituted with C₁₋₆ alkyl, amido, or (lower alkyl) amide; (iii)amino optionally mono- or di-substituted with C₁₋₆ alkyl; amido; or(lower alkyl)amide; (iv) C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl, all optionallysubstituted with C₁₋₆ alkyl, hydroxy, amido, (lower alkyl)amide, oramino optionally mono- or di-substituted with C₁₋₆ alkyl; or (v) Het or(lower alkyl)-Het, both optionally substituted with C₁₋₆ alkyl, hydroxy,amido, (lower alkyl) amide, or amino optionally mono- or di-substitutedwith C₁₋₆ alkyl; R₅ is H or C₁₋₆ alkyl; with the proviso that when R₄ isan amide or a thioamide, R₄ is not (ii) a cycloalkoxy; Y is H or C₁₋₆alkyl; R₃ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, or C₄₋₁₀ alkylcycloalkyl, alloptionally substituted with hydroxy, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, amido,(lower alkyl)amido, C₆ or C₁₀ aryl, or C₇₋₁₆ aralkyl; R₂ is CH₂—R₂₀,NH—R₂₀, O—R₂₀ or S—R₂₀, wherein R₂₀ is a saturated or unsaturated C₃₋₇cycloalkyl or C₄₋₁₀ (alkylcycloalkyl), all of which being optionallymono-, di- or tri-substituted with R₂₁, or R₂₀ is a C₆ or C₁₀ aryl orC₇₋₁₄ aralkyl, all optionally mono-, di- or tri-substituted with R₂₁, orR₂₀ is Het or (lower alkyl)-Het, both optionally mono-, di- ortri-substituted with R₂₁, wherein each R₂₁ is independently C₁₋₆ alkyl;C₁₋₆ alkoxy; lower thioalkyl; sulfonyl; N0₂; OH; SH; halo; haloalkyl;amino optionally mono- or di-substituted with C₁₋₆ alkyl, C₆ or C₁₀aryl, C₇₋₁₄ aralkyl, Het or (lower alkyl)-Het; amido optionallymono-substituted with C₁₋₆ alkyl, C₆ or C₁₀ aryl, C₇₋₁₄ aralkyl, Het or(lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C₆ or C₁₀ aryl, C₇₋₁₄aralkyl or Het, said aryl, aralkyl or Het being optionally substitutedwith R₂₂; wherein R₂₂ is C₁₋₆ alkyl; C₃₋₇ cycloalkyl; C₁₋₆ alkoxy; aminooptionally mono- or di-substituted with C₁₋₆ alkyl; sulfonyl; (loweralkyl)sulfonyl; N0₂; OH; SH; halo; haloalkyl; carboxyl; amide; (loweralkyl)amide; or Het optionally substituted with C₁₋₆ alkyl; R1 is H;C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, alloptionally substituted with halogen. w. Formula XXII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinW is CH or N, R²¹ is H, halo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, hydroxy, or N(R²³)₂, whereineach R²³ is independently H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; R²² is H,halo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ thioalkyl, C₁₋₆alkoxy, C₃₋₆ cycloalkoxy, C₂₋₇ alkoxyalkyl, C₃₋₆cycloalkyl, C_(6 or 10)aryl or Het, wherein Het is a five-, six-, or seven-membered saturatedor unsaturated heterocycle containing from one to four heteroatomsselected from nitrogen, oxygen and sulfur; said cycloalkyl, aryl or Hetbeing substituted with R²⁴, wherein R²⁴ is H, halo, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, NO₂, N(R²⁵)₂, NH—C(O)—R²⁵ orNH—C(O)—NH—R²⁵, wherein each R²⁵ is independently: H, C₁₋₆ alkyl or C₃₋₆cycloalkyl; or R²⁴ is NH—C(O)—OR²⁶ wherein R²⁶ is C₁₋₆ alkyl or C₃₋₆cycloalkyl; R³ is hydroxy, NH₂, or a group of formula —NH—R³¹ whereinR³¹ is C_(6 or 10) aryl, heteroaryl, —C(O)—R³², —C(O)—NHR³² or—C(O)—OR³², wherein R³² is C₁₋₆ alkyl or C₃₋₆ cycloalkyl; D is a 5 to10-atom saturated or unsaturated alkylene chain optionally containingone to three heteroatoms independently selected from: O, S, or N—R⁴¹,wherein R⁴¹ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or —C(O)—R⁴², wherein R⁴²is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or C_(6 or 10) aryl; R⁴ is H or from oneto three substituents at any carbon atom of said chain D, saidsubstituent independently selected from the group consisting of: C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, hydroxy, halo, amino, oxo, thio andC1-6 thioalkyl, and A is an amide of formula —C(O)—NH—R⁵, wherein R⁵ isselected from the group consisting of: C₁₋₈ alkyl, C₃₋₆ cycloalkyl,C_(6 or 10) aryl and C₇₋₁₆ aralkyl; or A is a carboxylic acid. x.Formula XXIII:

a pharmaceutically acceptable salt, solvate or ester thereof; wherein inFormula XXIII above: R⁰ is a bond or difluoromethylene; R¹ is hydrogen;R² and R⁹ are each independently optionally substituted aliphatic group,optionally substituted cyclic group or optionally substituted aromaticgroup; R3, R5 and R7 are each independently: optionally substituted(1,1- or 1,2-)cycloalkylene; or optionally substituted (1,1- or1,2-)heterocyclylene; or methylene or ethylene), substituted with onesubstituent selected from the group consisting of an optionallysubstituted aliphatic group, an optionally substituted cyclic group oran optionally substituted aromatic group, and wherein the methylene orethylene is further optionally substituted with an aliphatic groupsubstituent; or; R4, R6, R8 and R10 are each independently hydrogen oroptionally substituted aliphatic group;

is substituted monocyclic azaheterocyclyl or optionally substitutedmulticyclic azaheterocyclyl, or optionally substituted multicyclicazaheterocyclenyl wherein the unsaturatation is in the ring distal tothe ring bearing the R⁹-L-(N(R⁸)—R⁷—C(O)—)_(n)N(R⁶)—R⁵—C(O)—N moiety andto which the —C(O)—N(R⁴)—R³—C(O)C(O)NR²R¹ moiety is attached; L is—C(O)—, —OC(O)—, —NR¹⁰C(O)—, —S(O)₂—, or —NR¹⁰S(O)₂—; and n is 0 or 1,provided when

is substituted

then L is —OC(O)— and R⁹ is optionally substituted aliphatic; or atleast one of R³, R⁵ and R⁷ is ethylene, substituted with one substituentselected from the group consisting of an optionally substitutedaliphatic group, an optionally substituted cyclic group or an optionallysubstituted aromatic group and wherein the ethylene is furtheroptionally substituted with an aliphatic group substituent; or R⁴ isoptionally substituted aliphatic; y. Formula XXIV:

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XXIV above: W is:

m is 0 or 1; R² is independently hydrogen, alkyl, alkenyl, aryl,aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl,heteroaryl, or heteroaralkyl, wherein any R² carbon atom is optionallysubstituted with J; J is alkyl, aryl, aralkyl, alkoxy, aryloxy,aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy,heterocyclylalkyl, keto, hydroxy, amino, alkylamino, alkanoylamino,aroylamino, aralkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl,halo, cyano, nitro, formyl, acyl, sulfonyl, or sulfonamido and isoptionally substituted with 1-3 J¹ groups; J¹ is alkyl, aryl, aralkyl,alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, amino,alkanoylamino, aroylamino, carboxy, carboxyalkyl, carboxamidoalkyl,halo, cyano, nitro, formyl, sulfonyl, or sulfonamido; L is alkyl,alkenyl, or alkynyl, wherein any hydrogen is optionally substituted withhalogen, and wherein any hydrogen or halogen atom bound to any terminalcarbon atom is optionally substituted with sulfhydryl or hydroxy; A¹ isa bond; R⁴ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, orcarboxamidoalkyl, and is optionally substituted with 1-3 J groups; R⁵and R⁶ are independently hydrogen, alkyl, alkenyl, aryl, aralkyl,aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionallysubstituted with 1-3 J groups; X is a bond, —C(H)(R7)-, -0-, —S—, or—N(R8)-; R⁷ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionallysubstititued with 1-3 J groups; R⁸ is hydrogen alkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, aralkanoyl,heterocyclanoyl, heteroaralkanoyl, —C(O)R¹⁴, —S0₂R¹⁴, or carboxamido,and is optionally substititued with 1-3 J groups; or R⁸ and Z, togetherwith the atoms to which they are bound, form a nitrogen containing mono-or bicyclic ring system optionally substituted with 1-3 J groups; R¹⁴ isalkyl, aryl, aralkyl, heterocyclyl, heterocyclyalkyl, heteroaryl, orheteroaralkyl; Y is a bond, —CH₂—, —C(O)—, —C(O)C(O)—, —S(O)—, —S(O)₂—,or —S(O)(NR⁷)—, wherein R⁷ is as defined above; Z is alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, —OR², or —N(R²)₂, wherein any carbon atom isoptionally substituted with J, wherein R² is as defined above; A² is abond or

R⁹ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and isoptionally substituted with 1-3 J groups; M is alkyl, cycloalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl,optionally substituted by 1-3 J groups, wherein any alkyl carbon atommay be replaced by a heteroatom; V is a bond, —CH₂—, —C(H)(R¹¹)—, -0-,—S—, or —N(R¹¹)—; R¹¹ is hydrogen or C₁₋₃ alkyl; K is a bond, -0-, —S—,—C(O)—, —S(O)—, —S(O)₂—, or —S(O)(NR¹¹)—, wherein R¹¹ is as definedabove; T is —R¹², -alkyl-R¹², -alkenyl-R¹², -alkynyl-R¹², —OR¹²,—N(R¹²)₂, —C(O)R¹², —C(═NOalkyl)R¹², or

R¹² is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl,cycloalkylidenyl, or heterocycloalkylidenyl, and is optionallysubstituted with 1-3 J groups, or a first R¹² and a second R¹², togetherwith the nitrogen to which they are bound, form a mono- or bicyclic ringsystem optionally substituted by 1-3 J groups; R¹⁰ is alkyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionallysubstituted with 1-3 hydrogens J groups; R¹⁵ is alkyl, cycloalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl,carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with1-3 J groups; and R¹⁶ is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl,or heterocyclyl; and z. z. Formula XXV

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinE represents CHO or B(OH)₂; R¹ represents lower alkyl, halo-lower alkyl,cyano-lower alkyl, lower alkylthio-lower alkyl, aryl-loweralkylthio-lower alkyl, aryl-lower alkyl, heteroaryllower alkyl, loweralkenyl or lower alkynyl; R² represents lower alkyl, hydroxy-loweralkyl, carboxylower alkyl, aryl-lower alkyl, aminocarbonyl-lower alkylor lower cycloalkyl-lower alkyl; and R³ represents hydrogen or loweralkyl; or R² and R³ together represent di- or trimethylene optionallysubstituted by hydroxy; R⁴ represents lower alkyl, hydroxy-lower alkyl,lower cycloalkyl-lower alkyl, carboxy-lower alkyl, aryllower alkyl,lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl,aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl or lowercycloalkyl; R⁵ represents lower alkyl, hydroxy-lower alkyl, loweralkylthio-lower alkyl, aryl-lower alkyl, aryl-lower alkylthio-loweralkyl, cyano-lower alkylthio-lower alkyl or lower cycloalkyl; R⁶represents hydrogen or lower alkyl; R⁷ represent lower alkyl,hydroxydower alkyl, carboxylower alkyl, aryl-iower alkyl, lowercycloalkyl-lower alkyl or lower cycloalkyl; R⁸ represents lower alkyl,hydroxy-lower alkyl, carboxylower alkyl or aryl-lower alkyl; and R⁹represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl,arylcarbonyl, lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonylor aryl-lower alkoxycarbonyl. z1. Formula XXVI:

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XXVI above B is an acyl derivative of formula R₁₁—C(O)—wherein R₁₁ is Cl-10 alkyl optionally substituted with carboxyl; or R₁₁is C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substituted with a C₁₋₆alkyl; a is 0 or 1; R₆, when present, is carboxy(lower)alkyl; bis 0 or1; R₅, when present, is C₁₋₆ alkyl, or carboxy(lower)alkyl; Y is H orC₁₋₆ alkyl; R₄ is C₁₋₁₀ alkyl; C₃₋₁₀ cycloalkyl; R₃ is C₁₋₁₀ alkyl;C₃₋₁₀ cycloalkyl; W is a group of formula:

wherein R₂ is C₁₋₁₀ alkyl or C₃₋₇ cycloalkyl optionally substituted withcarboxyl; C₆ or C₁₀ aryl; or C₇₋₁₆ aralkyl; or W is a group of formula:

wherein X is CH or N; and R₂′ is C₃₋₄ alkylene that joins X to form a 5-or 6-membered ring, said ring optionally substituted with OH; SH; NH2;carboxyl; R₁₂; OR₁₂, SR₁₂, NHR₁₂ or NR₁₂R₁₂′ wherein R₁₂ and R₁₂′ areindependently: cyclic C₃₋₁₆ alkyl or acyclic C₁₋₁₆ alkyl or cyclic C₃₋₁₆alkenyl or acyclic C₂₋₁₆ alkenyl, said alkyl or alkenyl optionallysubstituted with NH₂, OH, SH, halo, or carboxyl; said alkyl or alkenyloptionally containing at least one heteroatom selected independentlyfrom the group consisting of: 0, S, and N; or R₁₂ and R₁₂′ areindependently C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substitutedwith C₁₋₆ alkyl, NH₂, OH, SH, halo, carboxyl or carboxy(lower)alkyl;said aryl or aralkyl optionally containing at least one heteroatomselected independently from the group consisting of: 0, S, and N; saidcyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fusedwith a second 5-, 6-, or 7-membered ring to form a cyclic system orheterocycle, said second ring being optionally substituted with NH₂. OH,SH, halo, carboxyl or carboxy(lower)alkyl; C₆ or C₁₀ aryl, orheterocycle; said second ring optionally containing at least oneheteroatom selected independently from the group consisting of: 0, S,and N; Q is a group of the formula:

wherein Z is CH; X is 0 or S; R₁ is H, C₁₋₆ alkyl or C₁₋₆ alkenyl bothoptionally substituted with thio or halo; and R₁₃ is C0-NH—R₁₄ whereinR₁₄ is hydrogen, cyclic C₃₋₁₀ alkyl or acyclic C₁₋₁₀ alkyl or cyclicC₃₋₁₀ alkenyl or acyclic C₂₋₁₀ alkenyl, said alkyl or alkenyl optionallysubstituted with NH₂, OH, SH, halo or carboxyl; said alkyl or alkenyloptionally containing at least one heteroatom selected independentlyfrom the group consisting of: 0, S, and N; or R₁₄ is C₆ or C₁₀ aryl orC₇₋₁₆aralkyl optionally substituted with C₁₋₆ alkyl, NH₂, OH, SH, halo,carboxyl or carboxy(lower)alkyl or substituted with a further C₃₋₇cycloalkyl, C₆ or C₁₀ aryl, or heterocycle; said aryl or aralkyloptionally containing at least one heteroatom selected independentlyfrom the group consisting of: 0, S, and N; said cyclic alkyl, cyclicalkenyl, aryl or aralkyl being optionally fused with a second 5-, 6-, or7-membered ring to form a cyclic system or heterocycle, said second ringbeing optionally substituted with NH₂, OH, SH, halo, carboxyl orcarboxy(lower)alkyl or substituted with a further C₃₋₇ cycloalkyl, C₆ orC₁₀ aryl, or heterocycle; said second ring optionally containing atleast one heteroatom selected independently from the group consistingof: 0, S, and N; with the proviso that when Z is CH, then R₁₃ is not anα-amino acid or an ester thereof; Q is a phosphonate group of theformula:

wherein R₁₅ and R₁₆ are independently C₆₋₂₀ aryloxy; and R₁ is asdefined above.
 3. A method of increasing the serum level of a compoundof Formulae I-XXVI in a subject comprising administering at least onecompound in combination with food, wherein the at least one compound isselected from the group consisting of compounds of Formulae I to XXVIbelow: a. Formula I

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinin Formula I above: Y is selected from the group consisting of thefollowing moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy,aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe optionallysubstituted with X¹¹ or X¹²; X¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with theproviso that X¹¹ may be additionally optionally substituted with X¹²;X¹² is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²; R¹is COR⁵, wherein R⁵ is COR⁷ wherein R⁷ is NHR⁹, wherein R⁹ is selectedfrom the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl,cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl,[CH(R^(1′))]_(p)COOR¹¹, [CH(R^(1′))]_(p)CONR¹²R¹³,[CH(R^(1′))]_(p)SO₂R¹¹, [CH(R^(1′))]_(p)COR¹¹,[CH(R^(1′))]_(p)CH(OH)R¹¹, CH(R^(1′))CONHCH(R²)COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONR¹²R¹³, CH(R^(1′) )CONHCH(R²)R′,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))COOR¹¹,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONR¹²R¹³,CH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))COOR¹¹andCH(R^(1′))CONHCH(R^(2′))CONHCH(R^(3′))CONHCH(R^(4′))CONHCH(R^(5′))CONR¹²R¹³,wherein R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), R¹¹, R¹², R¹³, and R′are independently selected from the group consisting of H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl,aryl-alkyl and heteroaralkyl; Z is selected from O, N, CH or CR; W maybepresent or absent, and if W is present, W is selected from C═O, C═S,C(═N—CN), or SO₂; Q maybe present or absent, and when Q is present, Q isCH, N, P, (CH₂)_(p), (CHR)_(p), (CRR′)_(p), O, NR, S, or SO₂; and when Qis absent, M may be present or absent; when Q and M are absent, A isdirectly linked to L; A is O, CH₂, (CHR)_(p), (CHR—CHR′)_(p),(CRR′)_(p), NR, S, SO₂ or a bond; E is CH, N, CR, or a double bondtowards A, L or G; G may be present or absent, and when G is present, Gis (CH₂)_(p), (CHR)_(p), or (CRR′)_(p); and when G is absent, J ispresent and E is directly connected to the carbon atom in Formula I as Gis linked to; J may be present or absent, and when J is present, J is(CH₂)_(p), (CHR)_(p), or (CRR′)_(p), SO₂, NH, NR or O; and when J isabsent, G is present and E is directly linked to N shown in Formula I aslinked to J; L may be present or absent, and when L is present, L is CH,CR, O, S or NR; and when L is absent, then M may be present or absent;and if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; M may be present or absent, and when M is present, M is O, NR, S,SO₂, (CH₂)_(p), (CHR)_(p)(CHR—CHR′)_(p), or (CRR′)_(p); p is a numberfrom 0 to 6; and R, R′, R², R³ and R⁴ are independently selected fromthe group consisting of H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₃-C₈cycloalkyl; C₃-C₈ heterocycloalkyl, alkoxy, aryloxy, alkylthio,arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone,aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms; aryl;heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl,heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl moieties may be optionally and chemically-suitablysubstituted, with said term “substituted” referring to optional andchemically-suitable substitution with one or more moieties selected fromthe group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl,cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy,alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate,urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone,sulfonyl urea, hydrazide, and hydroxamate; further wherein said unitN—C-G-E-L-J-N represents a five-membered or six-membered cyclic ringstructure with the proviso that when said unit N—C-G-E-L-J-N representsa five-membered cyclic ring structure, or when the bicyclic ringstructure in Formula I comprising N, C, G, E, L, J, N, A, Q, and Mrepresents a five-membered cyclic ring structure, then saidfive-membered cyclic ring structure lacks a carbonyl group as part ofthe cyclic ring; b. Formula II

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula II above: Z is NH; X is alkylsulfonyl, heterocyclylsulfonyl,heterocyclylalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,alkyaminocarbonyl, heterocyclylaminocarbonyl, arylaminocarbonyl, orheteroarylaminocarbonyl moiety, with the proviso that X may beadditionally optionally substituted with R¹² or R¹³; X¹ is H; C₁-C₄straight chain alkyl; C₁-C₄ branched alkyl or; CH₂-aryl (substituted orunsubstituted); R¹² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl moiety, withthe proviso that R¹² may be additionally optionally substituted withR¹³. R¹³ is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitromoiety, with the proviso that the alkyl, alkoxy, and aryl may beadditionally optionally substituted with moieties independently selectedfrom R¹³. P1a, P1b, P2, P3, P4, P5, and P6 are independently: H; C1-C10straight or branched chain alkyl; C2-C10 straight or branched chainalkenyl; C3-C8 cycloalkyl, C3-C8 heterocyclic; (cycloalkyl)alkyl or(heterocyclyl)alkyl, wherein said cycloalkyl is made up of 3 to 8 carbonatoms, and zero to 6 oxygen, nitrogen, sulfur, or phosphorus atoms, andsaid alkyl is of 1 to 6 carbon atoms; aryl, heteroaryl, arylalkyl, orheteroarylalkyl, wherein said alkyl is of 1 to 6 carbon atoms; whereinsaid alkyl, alkenyl, cycloalkyl, heterocyclyl; (cycloalkyl)alkyl and(heterocyclyl)alkyl moieties may be optionally substituted with R¹³, andfurther wherein said P1a and P1b may optionally be joined to each otherto form a spirocyclic or spiroheterocyclic ring, with said spirocyclicor spiroheterocyclic ring containing zero to six oxygen, nitrogen,sulfur, or phosphorus atoms, and may be additionally optionallysubstituted with R¹³; and P1′ is H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclyl-alkyl, aryl, aryl-alkyl,heteroaryl, or heteroaryl-alkyl; with the proviso that said P1′ may beadditionally optionally substituted with R¹³; c. Formula III

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula III above: G is carbonyl; J and Y may be the same ordifferent and are independently selected from the group consisting ofthe moieties: H, alkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy,aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe additionallyoptionally substituted with X¹¹ or X¹²; X¹¹ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl moiety, with the proviso that X¹¹may be additionally optionally substituted with X¹²; X¹² is hydroxy,alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino,arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²; R¹is COR⁵ or B(OR)₂, wherein R⁵ is selected from the group consisting ofH, OH, OR⁸, NR⁹R¹⁰, CF₃, C₂F₅, C₃F₇, CF₂R⁶, R⁶ and COR⁷ wherein R⁷ isselected from the group consisting of H, OH, OR⁸, CHR⁹R¹⁰, and NR⁹R¹⁰,wherein R⁶, R⁸, R⁹ and R¹⁰ may be the same or different and areindependently selected from the group consisting of H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl,heteroarylalkyl, CH(R^(1,))COOR¹¹, CH(R^(1,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))COOR¹¹, CH(R^(1′))CONHCH(R^(2′))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))R′,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))COOR¹¹,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))COOR¹¹,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))CONR¹²R¹³,CH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4′))CONHCH(R^(5,))COOR¹¹,andCH(R^(1,))CONHCH(R^(2,))CONHCH(R^(3,))CONHCH(R^(4,))CONHCH(R^(5,))CONR¹²R¹³,wherein R^(1,),R^(2,), R^(3,), R^(4,), R^(5,), R¹¹, R¹², R¹³, and R′ maybe the same or different and are independently selected from a groupconsisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl,alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; Z isselected from O, N, or CH; W maybe present or absent, and if W ispresent, W is selected from C═O, C═S, or SO₂; and R, R′, R², R³ and R⁴are independently selected from the group consisting of H; C1-C10 alkyl;C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro; oxygen, nitrogen,sulfur, or phosphorus atoms (with said oxygen, nitrogen, sulfur, orphosphorus atoms numbering zero to six); (cycloalkyl)alkyl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms; aryl;heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl,heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl andheterocycloalkyl moieties may be optionally substituted, with said term“substituted” referring to optional and chemically-suitable substitutionwith one or more moieties selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen,hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido,ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,sulfonamide, sulfoxide, sulfone, sulfonylurea, hydrazide, andhydroxamate; d. Formula IV

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: Y is selected from the group consisting of the followingmoieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylaminoand heterocycloalkylamino, with the proviso that Y maybe optionallysubstituted with X¹¹ or X¹²; X¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with theproviso that X¹¹ may be additionally optionally substituted with X¹²;X¹² is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro,with the proviso that said alkyl, alkoxy, and aryl may be additionallyoptionally substituted with moieties independently selected from X¹²; R¹is selected from the following structures:

wherein k is a number from 0 to 5, which can be the same or different,R¹¹ denotes optional substituents, with each of said substituents beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, cycloalkyl, alkyl-aryl, heteroalkyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino,heterocycloalkylamino, hydroxy, thio, alkylthio, arylthio, amino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido,carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, and nitro,with the proviso that R¹¹ (when R¹¹≠H) maybe optionally substituted withX¹¹ or X¹²; Z is selected from O, N, CH or CR; W may be present orabsent, and if W is present, W is selected from C═O, C═S, C(═N—CN), orS(O₂); Q may be present or absent, and when Q is present, Q is CH, N, P,(CH₂)_(p), (CHR)_(p), (CRR′)_(p), O, N(R), S, or S(O₂); and when Q isabsent, M may be present or absent; when Q and M are absent, A isdirectly linked to L; A is O, CH₂, (CHR)_(p), (CHR—CHR′)_(p),(CRR′)_(p), N(R), S, S(O₂) or a bond; E is CH, N, CR, or a double bondtowards A, L or G; G may be present or absent, and when G is present, Gis (CH₂)_(p), (CHR)_(p), or (CRR′)_(p); and when G is absent, J ispresent and E is directly connected to the carbon atom in Formula I as Gis linked to; J may be present or absent, and when J is present, J is(CH₂)_(p), (CHR)_(p), or (CRR′)_(p), S(O₂), NH, N(R) or O; and when J isabsent, G is present and E is directly linked to N shown in Formula I aslinked to J; L may be present or absent, and when L is present, L is CH,C(R), O, S or N(R); and when L is absent, then M may be present orabsent; and if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; M may be present or absent, and when M is present, M is O, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p)(CHR—CHR′)_(p), or (CRR′)_(p); p is a numberfrom 0 to 6; and R, R′, R², R³ and R⁴ can be the same or different, eachbeing independently selected from the group consisting of H; C₁-C₁₀alkyl; C₂-C₁₀ alkenyl; C₃-C₈ cycloalkyl; C₃-C₈ heterocycloalkyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro, halogen,(cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkylis made of three to eight carbon atoms, and zero to six oxygen,nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to sixcarbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionallysubstituted, with said term “substituted” referring to substitution withone or more moieties which can be the same or different, each beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy,thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester,carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, andhydroxamate; further wherein said unit N—C-G-E-L-J-N represents afive-membered cyclic ring structure or six-membered cyclic ringstructure with the proviso that when said unit N—C-G-E-L-J-N representsa five-membered cyclic ring structure, or when the bicyclic ringstructure in Formula I comprising N, C, G, E, L, J, N, A, Q, and Mrepresents a five-membered cyclic ring structure, then saidfive-membered cyclic ring structure lacks a carbonyl group as part ofsaid five-membered cyclic ring. e) Formula V

or a pharmaceutically acceptable salt, solvate or ester of said compoundwherein: (1) R¹ is —C(O)R⁵ or —B(OR)₂; (2) R⁵ is H, —OH, —OR⁸, —NR⁹R¹⁰,—C(O)OR⁸, —C(O)NR⁹R¹⁰, —CF₃, —C₂F₅, C₃F₇, —CF₂R⁶, —R⁶, —C(O)R⁷ orNR⁷SO₂R⁸; (3) R⁷ is H, —OH, —OR⁸, or —CHR⁹R¹⁰; (4) R⁶, R⁸, R⁹ and R¹⁰are independently selected from the group consisting of H: alkyl,alkenyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl,heteroarylalkyl, R¹⁴, —CH(R^(1′))CH(R^(1′))C(O)OR¹¹,[CH(R^(1′))]_(p)C(O)OR¹¹, —[CH(R^(1′))]_(p)C(O)NR¹²R¹³,—[CH(R^(1′))]_(p)S(O₂)R¹¹, —[CH(R^(1′))]_(p)C(O)R¹¹,—[CH(R^(1′))]_(p)S(O₂)NR¹²R¹³, CH(R^(1′))C(O)N(H)CH(R^(2′))(R′),CH(R^(1′))CH(R^(1′))C(O)NR¹²R¹³, —CH(R^(1′))CH(R^(1′))S(O₂)R¹¹,—CH(R^(1′))CH(R^(1′))S(O₂)NR¹²R¹³, —CH(R^(1′))CH(R^(1′))C(O)R¹¹,—[CH(R^(1′))]_(p)CH(OH)R¹¹, —CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)OR¹¹,C(O)N(H)CH(R^(2′))C(O)OR¹¹, —C(O)N(H)CH(R^(2′))C(O)R¹¹,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)NR¹²R¹³,—CH(R^(1′))C(O)N(H)CH(R^(2′))R′,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)OR¹¹,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)CH(R^(3′))NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)OR¹¹,H(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)NR¹²R¹³,CH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)N(H)CH(R^(5′))C(O)OR¹¹,andCH(R^(1′))C(O)N(H)CH(R^(2′))C(O)N(H)CH(R^(3′))C(O)N(H)CH(R^(4′))C(O)N(H)CH(R^(5′))C(O)NR¹²R¹³;wherein R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), R¹¹, R¹² and R¹³ can bethe same or different, each being independently selected from the groupconsisting of: H, halogen, alkyl, aryl, heteroalkyl, heteroaryl,cycloalkyl, alkoxy, aryloxy, alkenyl, alkynyl, alkyl-aryl,alkyl-heteroaryl, heterocycloalkyl, aryl-alkyl and heteroaralkyl; or R¹²and R¹³ are linked together wherein the combination is cycloalkyl,heterocycloalkyl, ary or heteroaryl; R¹⁴ is present or not and ifpresent is selected from the group consisting of: H, alkyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, allyl,alkyl-heteroaryl, alkoxy, aryl-alkyl, alkenyl, alkynyl andheteroaralkyl; (5) R and R′ are present or not and if present can be thesame or different, each being independently selected from the groupconsisting of: H, OH, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₃-C₈ cycloalkyl,C₃-C₈ heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio,alkylamino, arylamino, amino, amido, arylthioamino, arylcarbonylamino,arylaminocarboxy, alkylaminocarboxy, heteroalkyl, alkenyl, alkynyl,(aryl)alkyl, heteroarylalkyl, ester, carboxylic acid, carbamate, urea,ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl, aryl,heteroaryl, (alkyl)aryl, alkylheteroaryl, alkyl-heteroaryl and(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three toeight carbon atoms, and zero to six oxygen, nitrogen, sulfur, orphosphorus atoms, and said alkyl is of one to six carbon atoms; (6) L′is H, OH, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, orheterocyclyl; (7) M′ is H, alkyl, heteroalkyl, aryl, heteroaryl,cycloalkyl, arylalkyl, heterocyclyl or an amino acid side chain; or L′and M′ are linked together to form a ring structure wherein the portionof structural Formula 1 represented by

is represented by structural Formula 2:

wherein in Formula 2: E is present or absent and if present is C, CH, Nor C(R); J is present or absent, and when J is present, J is (CH₂)_(p),(CHR—CHR′)_(p), (CHR)_(p), (CRR′)_(p), S(O₂), N(H), N(R) or O; when J isabsent and G is present, L is directly linked to the nitrogen atommarked position 2; p is a number from 0 to 6; L is present or absent,and when L is present, L is C(H) or C(R); when L is absent, M is presentor absent; if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; G is present or absent, and when G is present, G is (CH₂)_(p),(CHR)_(p), (CHR—CHR′)_(p) or (CRR′)_(p); when G is absent, J is presentand E is directly connected to the carbon atom marked position 1; Q ispresent or absent, and when Q is present, Q is NR, PR, (CR═CR),(CH₂)_(p), (CHR)_(p), (CRR′)_(p), (CHR—CHR′)_(p), O, NR, S, SO, or SO₂;when Q is absent, M is (i) either directly linked to A or (ii) anindependent substituent on L, said independent substituent bing selectedfrom —OR, —CH(R)(R′), S(O)₀₋₂R or —NRR′ or (iii) absent; when both Q andM are absent, A is either directly linked to L, or A is an independentsubstituent on E, said independent substituent bing selected from —OR,—CH(R)(R′), S(O)₀₋₂R or —NRR′ or A is absent; A is present or absent andif present A is O, O(R), (CH₂)_(p), (CHR)_(p), (CHR—CHR′)_(p),(CRR′)_(p), N(R), NRR′, S, S(O₂), —OR, CH(R)(R′) or NRR′; or A is linkedto M to form an alicyclic, aliphatic or heteroalicyclic bridge; M ispresent or absent, and when M is present, M is halogen, O, OR, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p) (CHR—CHR′)_(p), or (CRR′)_(p); or M islinked to A to form an alicyclic, aliphatic or heteroalicyclic bridge;(8) Z′ is represented by the structural Formula 3:

wherein in Formula 3, Y is selected from the group consisting of: H,aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocycloalkyloxy, heteroalkyl-heteroaryl,heteroalkyl-heterocycloalkyl, cycloalkyloxy, alkylamino, arylamino,alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino andheterocycloalkylamino, and Y is unsubstituted or optionally substitutedwith one or two substituents which are the same or different and areindependently selected from X¹¹ or X¹²; X¹¹ is alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl,alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl,and X¹¹ is unsubstituted or optionally substituted with one or more ofX¹² moieties which are the same or different and are independentlyselected; X¹² is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl,aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,carbalkoxy, carboxamido, alkylcarbonyl, arylcarbonyl,heteroalkylcarbonyl, heteroarylcarbonyl, sulfonylurea,cycloalkylsulfonamido, heteroaryl-cycloalkylsulfonamido,heteroaryl-sulfonamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halogen, cyano, or nitro, and said alkyl,alkoxy, and aryl are unsubstituted or optionally independentlysubstituted with one or more moieties which are the same or differentand are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl; Z is O, N,C(H) or C(R); R³¹ is H, hydroxyl, aryl, alkyl, alkyl-aryl, heteroalkyl,heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy,alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy,heteroalkyl-heteroaryl, cycloalkyloxy, alkylamino, arylamino,alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino orheterocycloalkylamino, and R³¹ is unsubstituted or optionallysubstituted with one or two substituents which are the same or differentand are independently selected from X¹³ or X¹⁴; X¹³ is alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl,aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, orheteroarylalkyl, and X¹³ is unsubstituted or optionally substituted withone or more of X¹⁴ moieties which are the same or different and areindependently selected; X¹⁴ is hydroxy, alkoxy, alkyl, alkenyl, alkynyl,aryl, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,carbalkoxy, carboxamido, alkylcarbonyl, arylcarbonyl,heteroalkylcarbonyl, heteroarylcarbonyl, cycloalkylsulfonamido,heteroaryl-cycloalkylsulfonamido, heteroarylsulfonamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,halogen, cyano, or nitro, and said alkyl, alkoxy, and aryl areunsubstiuted or optionally independently substituted with one or moremoieties which are the same or different and are independently selectedfrom alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl,alkylheteroaryl, or heteroarylalkyl; W may be present or absent, and ifW is present, W is C(═O), C(═S), C(═N—CN), or S(O₂); (9) X isrepresented by structural Formula 4:

wherein in Formula 4, a is 2, 3, 4, 5, 6, 7, 8 or 9; b, c, d, e and fare 0, 1, 2, 3, 4 or 5; A is C, N, S or O; R²⁹ and R^(29′) areindependently present or absent and if present can be the same ordifferent, each being independently one or two substituentsindependently selected from the group consisting of: H, halo, alkyl,aryl, cycloalkyl, cycloalkylamino, cycloalkylaminocarbonyl, cyano,hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, carboxyl, C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl,aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl,hydroxyalkyl, aryloxy, aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl,heterocyclyl, heterocyclenyl, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—,wherein Y₁ and Y₂ can be the same or different and are independentlyselected from the group consisting of hydrogen, alkyl, aryl, andaralkyl; or R²⁹ and R^(29′) are linked together such that thecombination is an aliphatic or heteroaliphatic chain of 0 to 6 carbons;R³⁰ is present or absent and if present is one or two substituentsindependently selected from the group consisting of: H, alkyl, aryl,heteroaryl and cylcoalkyl; (10) D is represented by structural Formula5:

wherein in Formula 5, R³², R³³ and R³⁴ are present or absent and ifpresent are independently one or two substituents independently selectedfrom the group consisting of: H, halo, alkyl, aryl, cycloalkyl,cycloalkylamino, spiroalkyl, cycloalkylaminocarbonyl, cyano, hydroxy,alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂,carboxyl, —C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl, aralkenyl,heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxyalkyl, aryloxy,aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl,arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkenyl, heterocyclyl, heterocyclenyl,Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ can be thesame or different and are independently selected from the groupconsisting of hydrogen, alkyl, aryl, and aralkyl; or R³² and R³⁴ arelinked together such that the combination forms a portion of acycloalkyl group; g is 1, 2, 3, 4, 5, 6, 7, 8 or 9; h, i, j, k, l and mare 0, 1, 2, 3, 4 or 5; and A is C, N, S or O, (11) provided that whenstructural Formula 2:

W′ is CH or N, both the following conditional exclusions (i) and (ii)apply: conditional exclusion (i): Z′ is not —NH—R³⁶, wherein R³⁶ is H,C_(6 or 10) aryl, heteroaryl, —C(O)—R³⁷, —C(O)—OR³⁷ or —C(O)—NHR³⁷,wherein R³⁷ is C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and conditional exclusion(ii): R¹ is not —C(O)OH, a pharmaceutically acceptable salt of —C(O)OH,an ester of —C(O)OH or —C(O)NHR³⁸ wherein R³⁸ is selected from the groupconsisting of C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C_(6 to 10) aryl or C₇₋₁₆aralkyl. f. Formula VI

or a pharmaceutically acceptable salt, solvate or ester of saidcompound, wherein in Formula VI above: Cap is H, alkyl, alkyl-aryl,heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl,alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy,cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy orheterocyclylamino, wherein each of said alkyl, alkyl-aryl, heteroalkyl,heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy,alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy,amino, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy orheterocyclylamino can be unsubstituted or optionally independentlysubstituted with one or two substituents which can be the same ordifferent and are independently selected from X¹ and X²; P′is —NHR; X¹is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl,heteroaryl, heterocyclylamino, alkylheteroaryl, or heteroarylalkyl, andX¹ can be unsubstituted or optionally independently substituted with oneor more of X² moieties which can be the same or different and areindependently selected; X² is hydroxy, alkyl, aryl, alkoxy, aryloxy,thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halogen, cyano, keto, ester or nitro, wherein each of saidalkyl, alkoxy, and aryl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same or differentand are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino,alkylheteroaryl and heteroarylalkyl; W may be present or absent, andwhen W is present W is C(═O), C(═S), C(═NH), C(═N—OH), C(═N—CN), S(O) orS(O₂); Q maybe present or absent, and when Q is present, Q is N(R),P(R), CR═CR′, (CH₂)_(p), (CHR)_(p), (CRR′)_(p), (CHR—CHR′)_(p), O, S,S(O) or S(O₂); when Q is absent, M is (i) either directly linked to A or(ii) M is an independent substituent on L and A is an independentsubstituent on E, with said independent substituent being selected from—OR, —CH(R), S(O)₀₋₂R or —NRR′; when both Q and M are absent, A iseither directly linked to L, or A is an independent substituent on E,selected from —OR, CH(R)(R′), —S(O)₀₋₂R or —NRR′; A is present or absentand if present A is —O—, —O(R)CH₂—, —(CHR)_(p)—, —(CHR—CHR′)_(p)—,(CRR′)_(p), N(R), NRR′, S, or S(O₂), and when Q is absent, A is —OR,—CH(R)(R′) or —NRR′; and when A is absent, either Q and E are connectedby a bond or Q is an independent substituent on M; E is present orabsent and if present E is CH, N, C(R); G may be present or absent, andwhen G is present, G is (CH₂)_(p), (CHR)_(p), or (CRR′)_(p); when G isabsent, J is present and E is directly connected to the carbon atommarked position 1; J may be present or absent, and when J is present, Jis (CH₂)_(p), (CHR—CHR′)_(p), (CHR)_(p), (CRR′)_(p), S(O₂), N(H), N(R)or O; when J is absent and G is present, L is directly linked to thenitrogen atom marked position 2; L may be present or absent, and when Lis present, L is CH, N, or CR; when L is absent, M is present or absent;if M is present with L being absent, then M is directly andindependently linked to E, and J is directly and independently linked toE; M may be present or absent, and when M is present, M is O, N(R), S,S(O₂), (CH₂)_(p), (CHR)_(p), (CHR—CHR′)_(p), or (CRR′)_(p); p is anumber from 0 to 6; R, R′ and R³ can be the same or different, eachbeing independently selected from the group consisting of: H, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, arylthioamino,arylcarbonylamino, arylaminocarboxy, alkylaminocarboxy, heteroalkyl,heteroalkenyl, alkenyl, alkynyl, aryl-alkyl, heteroarylalkyl, ester,carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,halogen, (cycloalkyl)alkyl, aryl, heteroaryl, alkyl-aryl,alkylheteroaryl, alkyl-heteroaryl and (heterocyclyl)alkyl; R and R′ in(CRR′) can be linked together such that the combination forms acycloalkyl or heterocyclyl moiety; and R¹ is carbonyl; g. Formula VII

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein, M is O, N(H), or CH₂; n is 0-4; R¹ is −OR⁶, —NR⁶R⁷ or

where R⁶ and R⁷ can be the same or different, each being independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino,arylamino and alkylamino; R⁴ and R⁵ can be the same or different, eachbeing independently selected from the group consisting of H, alkyl, aryland cycloalkyl; or alternatively R⁴ and R⁵ together form part of acyclic 5- to 7-membered ring such that the moiety

is represented by

where k is 0 to 2; X is selected from the group consisting of:

where p is 1 to 2, q is 1-3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and R³ is selected from the group consisting of: aryl,heterocyclyl, heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy. h. Formula VIII

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinin Formula VIII above, M is O, N(H), or CH₂; R¹ is —C(O)NHR⁶, where R⁶is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, hydroxyl, amino, arylamino oralkylamino; P₁ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl haloalkyl; P₃ is selected from the group consistingof alkyl, cycloalkyl, aryl and cycloalkyl fused with aryl; R⁴ and R⁵ canbe the same or different, each being independently selected from thegroup consisting of H, alkyl, aryl and cycloalkyl; or alternatively R⁴and R⁵ together form part of a cyclic 5- to 7-membered ring such thatthe moiety

is represented by

where k is 0 to 2; X is selected from the group consisting of:

where p is 1 to 2, q is 1 to 3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and R³ is selected from the group consisting of: aryl,heterocyclyl, heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy; i. formula IX:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein, M is O, N(H), or CH₂; n is 0-4; R¹ is —OR⁶, —NR⁶R⁷ or

where R⁶ and R⁷ can be the same or different, each being independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino,arylamino and alkylamino; R⁴ and R⁵ can be the same or different, eachbeing independently selected from the group consisting of H, alkyl, aryland cycloalkyl; or alternatively R⁴ and R⁵ together form part of acyclic 5- to 7-membered ring such that the moiety

is represented by

where k is 0 to 2; X is selected from the group consisting of:

where p is 1 to 2, q is 1 to 3 and P² is alkyl, aryl, heteroaryl,heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino orcycloalkylamino; and R³ is selected from the group consisting of: aryl,heterocyclyl, heteroaryl,

where Y is O, S or NH, and Z is CH or N, and the R⁸ moieties can be thesame or different, each R⁸ being independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino,dialkylamino, halo, alkylthio, arylthio and alkyloxy; j. Formula X

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula X above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, R¹⁵ and R¹⁶ are connected to eachother to form a four to eight-membered cycloalkyl, heteroaryl orheterocyclyl structure, and likewise, independently R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; k. Formula XI

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XI above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, NR⁹R¹⁰, SR, SO₂R, and halo; orA and M are connected to each other (in other words, A-E-L-M takentogether) such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NR⁹R¹⁰ forms afour to eight-membered heterocyclyl; Y is selected from the followingmoieties:

wherein Y³⁰ and Y³¹ are selected from

where u is a number 0-6; X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O)and SO₂; G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, T₃ and T₄can be the same or different, each being independently selected from thegroup consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl,alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl, or alternately, R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; l. Formula XII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XII above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately, (i) either R¹⁵ and R¹⁶ areconnected to each other to form a four to eight-membered cyclicstructure, or R¹⁵ and R¹⁹ are connected to each other to form a four toeight-membered cyclic structure, and (ii) likewise, independently, R¹⁷and R¹⁸ are connected to each other to form a three to eight-memberedcycloalkyl or heterocyclyl; wherein each of said alkyl, aryl,heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of: □ulfonam, alkoxy, aryloxy, thio,alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, □ulfonamide, alkylsulfonamido, arylsulfonamido, alkyl,aryl, heteroaryl, keto, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo,cyano, and nitro; m. Formula XIII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XIII above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other (in other words, A-E-L-Mtaken together) such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; and Y is selected from the followingmoieties:

wherein G is NH or O, and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ can be thesame or different, each being independently selected from the groupconsisting of H, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ heteroalkenyl, C₂-C₁₀ alkynyl, C₂-C₁₀ heteroalkynyl, C₃-C₈cycloalkyl, C₃-C₈ heterocyclyl, aryl, heteroaryl, or alternately: (i)either R¹⁵ and R¹⁶ can be connected to each other to form a four toeight-membered cycloalkyl or heterocyclyl, or R¹⁵ and R¹⁹ are connectedto each other to form a five to eight-membered cycloalkyl orheterocyclyl, or R¹⁵ and R²⁰ are connected to each other to form a fiveto eight-membered cycloalkyl or heterocyclyl, and (ii) likewise,independently, R¹⁷ and R¹⁸ are connected to each other to form a threeto eight-membered cycloalkyl or heterocyclyl, wherein each of saidalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstitutedor optionally independently substituted with one or more moietiesselected from the group consisting of: hydroxy, alkoxy, aryloxy, thio,alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, keto,carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro; n.Formula XIV

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XIV above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately R and R′ in NRR′ are connected toeach other such that NRR′ forms a four to eight-membered heterocyclyl;and Y is selected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷ and R¹⁸ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, oralternately, (i) R¹⁵ and R¹⁶ are connected to each other to form a fourto eight-membered cyclic structure, and (ii) likewise, independently R¹⁷and R¹⁸ are connected to each other to form a three to eight-memberedcycloalkyl or heterocyclyl; wherein each of said alkyl, aryl,heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, alkyl,aryl, heteroaryl, keto, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo,cyano, and nitro; p. Formula XV

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XV above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, cycloalkyl-, arylalkyl-, orheteroarylalkyl; E and J can be the same or different, each beingindependently selected from the group consisting of R, OR, NHR, NRR⁷,SR, halo, and S(O₂)R, or E and J can be directly connected to each otherto form either a three to eight-membered cycloalkyl, or a three toeight-membered heterocyclyl moiety; Z is N(H), N═, or O, with theproviso that when Z is O, G is present or absent and if G is presentwith Z being O, then G is C(═O); G maybe present or absent, and if G ispresent, G is C(═O) or S(O₂), and when G is absent, Z is directlyconnected to Y; Y is selected from the group consisting of:

R, R⁷, R², R³, R⁴ and R⁵ can be the same or different, each beingindependently selected from the group consisting of H, alkyl-, alkenyl-,alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-,(cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, andheteroaryl-alkyl-, wherein each of said heteroalkyl, heteroaryl andheterocyclyl independently has one to six oxygen, nitrogen, sulfur, orphosphorus atoms; wherein each of said alkyl, heteroalkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl moieties can beunsubstituted or optionally independently substituted with one or moremoieties selected from the group consisting of alkyl, alkenyl, alkynyl,aryl, aralkyl, cycloalkyl, heterocyclyl, halo, hydroxy, thio, alkoxy,aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid,carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide,sulfone, sulfonyl urea, hydrazide, and hydroxamate; q. Formula XVI

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XVI above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; R² and R³ can be the same or different,each being independently selected from the group consisting of H, alkyl,heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Y isselected from the following moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³,R²⁴ and R²⁵ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R¹⁷ andR¹⁸ are independently connected to each other to form a three toeight-membered cycloalkyl or heterocyclyl; (ii) likewise independentlyR¹⁵ and R¹⁹ are connected to each other to form a four to eight-memberedheterocyclyl; (iii) likewise independently R¹⁵ and R¹⁶ are connected toeach other to form a four to eight-membered heterocyclyl; (iv) likewiseindependently R¹⁵ and R²⁰ are connected to each other to form a four toeight-membered heterocyclyl; (v) likewise independently R²² and R²³ areconnected to each other to form a three to eight-membered cycloalkyl ora four to eight-membered heterocyclyl; and (vi) likewise independentlyR²⁴ and R²⁵ are connected to each other to form a three toeight-membered cycloalkyl or a four to eight-membered heterocyclyl;wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclylcan be unsubstituted or optionally independently substituted with one ormore moieties selected from the group consisting of hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro; r. Formula XVII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XVII above: R¹ is NHR⁹, wherein R⁹ is H, alkyl-, alkenyl-,alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-,arylalkyl-, or heteroarylalkyl; A and M can be the same or different,each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, andhalo; or A and M are connected to each other such that the moiety:

shown above in Formula I forms either a three, four, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC═; L is C(H), C═, CH₂C═, or C═CH₂; R, R′, R², and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in NRR′ are connected to each other such that NRR′ forms a fourto eight-membered heterocyclyl; Y is selected from the followingmoieties:

wherein Y³⁰ is selected from

where u is a number 0-1; X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O)and SO₂; G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, and T₃ canbe the same or different, each being independently selected from thegroup consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl,alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl, or alternately, R¹⁷ and R¹⁸ areconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; s. Formula XVIII:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein: R⁸ is selected from the group consisting of alkyl-, aryl-,heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-,heteroarylalkyl-, and heterocyclylalkyl; R⁹ is selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl and cycloalkyl; A and Mcan be the same or different, each being independently selected from R,OR, N(H)R, N(RR′), SR, S(O₂)R, and halo; or A and M are connected toeach other (in other words, A-E-L-M taken together) such that themoiety:

shown above in Formula I forms either a three, four, five, six, seven oreight-membered cycloalkyl, a four to eight-membered heterocyclyl, a sixto ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) orC(R); L is C(H), C(R), CH₂C(R), or C(R)CH₂; R and R′ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-,heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,(heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternatelyR and R′ in N(RR′) are connected to each other such that N(RR′) forms afour to eight-membered heterocyclyl; R² and R³ can be the same ordifferent, each being independently selected from the group consistingof H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, spiro-linked cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl; Y is selected from thefollowing moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately (i) R¹⁷ and R¹⁸ are independentlyconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; (ii) likewise independently R¹⁵ and R¹⁹ are connected toeach other to form a four to eight-membered heterocyclyl; (iii) likewiseindependently R¹⁵ and R¹⁶ are connected to each other to form a four toeight-membered heterocyclyl; and (iv) likewise independently R¹⁵ and R²⁰are connected to each other to form a four to eight-memberedheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl,spiro-linked cycloalkyl, and heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties selectedfrom the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,arylsulfonyl, sulfonamido, alkyl, alkenyl, aryl, heteroaryl,alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,arylureido, halo, cyano, and nitro. t. Formula XIX

wherein in Formula XIX above: Z is selected from the group consisting ofa heterocyclyl moiety, N(H)(alkyl), —N(alkyl)₂, —N(H)(cycloalkyl),—N(cycloalkyl)₂, —N(H)(aryl, —N(aryl)₂, —N(H)(heterocyclyl),—N(heterocyclyl)₂, —N(H)(heteroaryl), and —N(heteroaryl)₂; R¹ is NHR⁹,wherein R⁹ is H, alkyl-, alkenyl-, alkynyl-, aryl-, heteroalkyl-,heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, or heteroarylalkyl;R² and R³ can be the same or different, each being independentlyselected from the group consisting of H, alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl; Y is selected from thefollowing moieties:

wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ can bethe same or different, each being independently selected from the groupconsisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl, or alternately (i) R¹⁷ and R¹⁸ are independentlyconnected to each other to form a three to eight-membered cycloalkyl orheterocyclyl; (ii) likewise independently R¹⁵ and R¹⁹ are connected toeach other to form a four to eight-membered heterocyclyl; (iii) likewiseindependently R¹⁵ and R¹⁶ are connected to each other to form a four toeight-membered heterocyclyl; and (iv) likewise independently R¹⁵ and R²⁰are connected to each other to form a four to eight-memberedheterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkylor heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties selected from the group consistingof hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido,alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl,aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halo, cyano, and nitro; u. Formula XX

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: a is 0 or 1; b is 0 or 1; Y is H or C₁₋₆alkyl; B is H, an acylderivative of formula R₇—C(O)— or a sulfonyl of formula R₇—SO2 whereinR7 is (i) C₁₋₁₀ alkyl optionally substituted with carboxyl, C₁₋₆alkanoyloxy or C₁₋₆ alkoxy; (ii) C₃₋₇ cycloalkyl optionally substitutedwith carboxyl, (C₁₋₆ alkoxy)carbonyl or phenylmethoxycarbonyl; (iii) C₆or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substituted with C₁₋₆ alkyl,hydroxy, or amino optionally substituted with C₁₋₆ alkyl; or (iv) Hetoptionally substituted with C₁₋₆ alkyl, hydroxy, amino optionallysubstituted with C₁₋₆ alkyl, or amido optionally substituted with C₁₋₆alkyl; R₆, when present, is C₁₋₆ alkyl substituted with carboxyl; R₅,when present, is C₁₋₆ alkyl optionally substituted with carboxyl; R₄ isC₁₋₁₀ alkyl, C₃₋₇ cycloalkyl or C₄₋₁₀ (alkylcycloalkyl); R₃ is C₁₋₁₀alkyl, C₃₋₇ cycloalkyl or C₄₋₁₀ (alkylcycloalkyl); R₂ is CH₂—R₂₀,NH—R₂₀, O—R₂₀ or S—R₂₀, wherein R₂₀ is a saturated or unsaturated C₃₋₇cycloalkyl or C₄₋₁₀ (alkyl cycloalkyl) being optionally mono-, di- ortri-substituted with R₂₁, or R₂₀ is a C₆ or C₁₀ aryl or C₇₋₁₆ aralkyloptionally mono-, di- or tri-substituted with R₂₁, or R₂₀ is Het or(lower alkyl)-Het optionally mono-, di- or tri-substituted with R₂₁,wherein each R₂₁ is independently C₁₋₆ alkyl; C₁₋₆alkoxy; aminooptionally mono- or di-substituted with C₁₋₆ alkyl; sulfonyl; N0₂; OH;SH; halo; haloalkyl; amido optionally mono-substituted with C₁₋₆ alkyl,C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl, Het or (lower alkyl)-Het; carboxyl;carboxy(lower alkyl); C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl or Het, said aryl,aralkyl or Het being optionally substituted with R₂₂; wherein R₂₂ isC₁₋₆alkyl; C₁₋₆ alkoxy; amino optionally mono- or di-substituted withC₁₋₆ alkyl; sulfonyl; N0₂; OH; SH; halo; haloalkyl; carboxyl; amide or(lower alkyl)amide; R₁ is C₁₋₆ alkyl or C₂₋₆ alkenyl optionallysubstituted with halogen; and W is hydroxy or a N-substituted amino. Inthe above-shown structure of the compound of Formula XX, the terms P6,P5, P4, P3, P2 and P1 denote the respective amino acid moieties as isconventionally known to those skilled in the art. v. Formula XXI

or a pharmaceutically acceptable salt, solvate or ester thereof;wherein: B is H, a C₆ or C₁₀ aryl, C₇₋₁₆ aralkyl; Het or (loweralkyl)-Het, all of which optionally substituted with C₁₋₆ alkyl; C₁₋₆alkoxy; C₁₋₆ alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro;cyano; cyanoalkyl; amino optionally substituted with C₁₋₆ alkyl; amido;or (lower alkyl)amide; or B is an acyl derivative of formula R₄—C(O)—; acarboxyl of formula R₄-0-C(O)—; an amide of formula R₄—N(R₅)—C(O)—; athioamide of formula R₄—N(R₅)—C(S)—; or a sulfonyl of formula R₄—SO2wherein R₄ is (i) C₁₋₁₀ alkyl optionally substituted with carboxyl, C₁₋₆alkanoyl, hydroxy, C₁₋₆ alkoxy, amino optionally mono- or di-substitutedwith C₁₋₆ alkyl, amido, or (lower alkyl) amide; (ii) C₃₋₇ cycloalkyl,C₃₋₇ cycloalkoxy, or C₄₋₁₀ alkylcycloalkyl, all optionally substitutedwith hydroxy, carboxyl, (C₁₋₆ alkoxy)carbonyl, amino optionally mono- ordi-substituted with C₁₋₆ alkyl, amido, or (lower alkyl) amide; (iii)amino optionally mono- or di-substituted with C₁₋₆ alkyl; amido; or(lower alkyl)amide; (iv) C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl, all optionallysubstituted with C₁₋₆ alkyl, hydroxy, amido, (lower alkyl)amide, oramino optionally mono- or di-substituted with C₁₋₆ alkyl; or (v) Het or(lower alkyl)-Het, both optionally substituted with C₁₋₆ alkyl, hydroxy,amido, (lower alkyl) amide, or amino optionally mono- or di-substitutedwith C₁₋₆ alkyl; R₅ is H or C₁₋₆ alkyl; with the proviso that when R₄ isan amide or a thioamide, R₄ is not (ii) a cycloalkoxy; Y is H or C₁₋₆alkyl; R₃ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, or C₄₋₁₀ alkylcycloalkyl, alloptionally substituted with hydroxy, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, amido,(lower alkyl)amido, C₆ or C₁₀ aryl, or C₇₋₁₆ aralkyl; R₂ is CH₂—R₂₀,NH—R₂₀, O—R₂₀ or S—R₂₀, wherein R₂₀ is a saturated or unsaturated C₃₋₇cycloalkyl or C₄₋₁₀ (alkylcycloalkyl), all of which being optionallymono-, di- or tri-substituted with R₂₁, or R₂₀ is a C₆ or C₁₀ aryl orC₇₋₁₄ aralkyl, all optionally mono-, di- or tri-substituted with R₂₁, orR₂₀ is Het or (lower alkyl)-Het, both optionally mono-, di- ortri-substituted with R₂₁, wherein each R₂₁ is independently C₁₋₆ alkyl;C₁₋₆ alkoxy; lower thioalkyl; sulfonyl; N0₂; OH; SH; halo; haloalkyl;amino optionally mono- or di-substituted with C₁₋₆ alkyl, C₆ or C₁₀aryl, C₇₋₁₄ aralkyl, Het or (lower alkyl)-Het; amido optionallymono-substituted with C₁₋₆ alkyl, C₆ or C₁₀ aryl, C₇₋₁₄ aralkyl, Het or(lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C₆ or C₁₀ aryl, C₇₋₁₄aralkyl or Het, said aryl, aralkyl or Het being optionally substitutedwith R₂₂; wherein R₂₂ is C₁₋₆ alkyl; C₃₋₇ cycloalkyl; C₁₋₆ alkoxy; aminooptionally mono- or di-substituted with C₁₋₆ alkyl; sulfonyl; (loweralkyl)sulfonyl; N0₂; OH; SH; halo; haloalkyl; carboxyl; amide; (loweralkyl)amide; or Het optionally substituted with C₁₋₆ alkyl; R1 is H;C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, alloptionally substituted with halogen. w. Formula XXII

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinW is CH or N, R²¹ is H, halo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, hydroxy, or N(R²³)₂, whereineach R²³ is independently H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; R²² is H,halo, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ thioalkyl, C₁₋₆alkoxy, C₃₋₆ cycloalkoxy, C₂₋₇ alkoxyalkyl, C₃₋₆cycloalkyl, C_(6 or 10)aryl or Het, wherein Het is a five-, six-, or seven-membered saturatedor unsaturated heterocycle containing from one to four heteroatomsselected from nitrogen, oxygen and sulfur; said cycloalkyl, aryl or Hetbeing substituted with R²⁴, wherein R²⁴ is H, halo, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, NO₂, N(R²⁵)₂, NH—C(O)—R²⁵ orNH—C(O)—NH—R²⁵, wherein each R²⁵ is independently: H, C₁₋₆ alkyl or C₃₋₆cycloalkyl; or R²⁴ is NH—C(O)—OR²⁶ wherein R²⁶ is C₁₋₆ alkyl or C₃₋₆cycloalkyl; R³ is hydroxy, NH₂, or a group of formula —NH—R³¹, whereinR³¹ is C_(6 or 10) aryl, heteroaryl, —C(O)—R³², —C(O)—NHR³² or—C(O)—OR³², wherein R³² is C₁₋₆ alkyl or C₃₋₆ cycloalkyl; D is a 5 to10-atom saturated or unsaturated alkylene chain optionally containingone to three heteroatoms independently selected from: O, S, or N—R⁴¹,wherein R⁴¹ is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or —C(O)—R⁴², wherein R⁴²is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or C_(6 or 10) aryl; R⁴ is H or from oneto three substituents at any carbon atom of said chain D, saidsubstituent independently selected from the group consisting of: C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, hydroxy, halo, amino, oxo, thio andC₁₋₆ thioalkyl, and A is an amide of formula —C(O)—NH—R⁵, wherein R⁵ isselected from the group consisting of: C₁₋₈ alkyl, C₃₋₆ cycloalkyl,C_(6 or 10) aryl and C₇₋₁₆ aralkyl; or A is a carboxylic acid. x.Formula XXIII:

a pharmaceutically acceptable salt, solvate or ester thereof; wherein inFormula XXIII above: R⁰ is a bond or difluoromethylene; R¹ is hydrogen;R² and R⁹ are each independently optionally substituted aliphatic group,optionally substituted cyclic group or optionally substituted aromaticgroup; R3, R5 and R7 are each independently: optionally substituted(1,1- or 1,2-)cycloalkylene; or optionally substituted (1,1- or1,2-)heterocyclylene; or methylene or ethylene), substituted with onesubstituent selected from the group consisting of an optionallysubstituted aliphatic group, an optionally substituted cyclic group oran optionally substituted aromatic group, and wherein the methylene orethylene is further optionally substituted with an aliphatic groupsubstituent; or; R4, R6, R8 and R¹⁰ are each independently hydrogen oroptionally substituted aliphatic group;

is substituted monocyclic azaheterocyclyl or optionally substitutedmulticyclic azaheterocyclyl, or optionally substituted multicyclicazaheterocyclenyl wherein the unsaturatation is in the ring distal tothe ring bearing the R⁹-L-(N(R⁸)—R⁷—C(O)—)_(n)N(R⁶)—R⁵—C(O)—N moiety andto which the —C(O)—N(R⁴)—R³—C(O)C(O)NR²R¹ moiety is attached; L is—C(O)—, —OC(O)—, —NR¹⁰C(O)—, —S(0)₂—, or —NR¹⁰S(0)₂—; and n is 0 or 1,provided when

is substituted

then L is —OC(O)— and R⁹ is optionally substituted aliphatic; or atleast one of R³, R⁵ and R⁷ is ethylene, substituted with one substituentselected from the group consisting of an optionally substitutedaliphatic group, an optionally substituted cyclic group or an optionallysubstituted aromatic group and wherein the ethylene is furtheroptionally substituted with an aliphatic group substituent; or R⁴ isoptionally substituted aliphatic; y. Formula XXIV:

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XXIV above: W is:

m is 0 or 1; R² is independently hydrogen, alkyl, alkenyl, aryl,aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl,heteroaryl, or heteroaralkyl, wherein any R² carbon atom is optionallysubstituted with J; J is alkyl, aryl, aralkyl, alkoxy, aryloxy,aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy,heterocyclylalkyl, keto, hydroxy, amino, alkylamino, alkanoylamino,aroylamino, aralkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl,halo, cyano, nitro, formyl, acyl, sulfonyl, or sulfonamido and isoptionally substituted with 1-3 J¹ groups; J¹ is alkyl, aryl, aralkyl,alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, amino,alkanoylamino, aroylamino, carboxy, carboxyalkyl, carboxamidoalkyl,halo, cyano, nitro, formyl, sulfonyl, or sulfonamido; L is alkyl,alkenyl, or alkynyl, wherein any hydrogen is optionally substituted withhalogen, and wherein any hydrogen or halogen atom bound to any terminalcarbon atom is optionally substituted with sulfhydryl or hydroxy; A¹ isa bond; R⁴ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, orcarboxamidoalkyl, and is optionally substituted with 1-3 J groups; R⁵and R⁶ are independently hydrogen, alkyl, alkenyl, aryl, aralkyl,aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionallysubstituted with 1-3 J groups; X is a bond, —C(H)(R7)-, -0-, —S—, or—N(R8)-; R⁷ is hydrogen, alkyl, alkenyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionallysubstititued with 1-3 J groups; R⁸ is hydrogen alkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, aralkanoyl,heterocyclanoyl, heteroaralkanoyl, —C(O)R¹⁴, —S0₂R¹⁴, or carboxamido,and is optionally substititued with 1-3 J groups; or R⁸ and Z, togetherwith the atoms to which they are bound, form a nitrogen containing mono-or bicyclic ring system optionally substituted with 1-3 J groups; R¹⁴ isalkyl, aryl, aralkyl, heterocyclyl, heterocyclyalkyl, heteroaryl, orheteroaralkyl; Y is a bond, —CH₂—, —C(O)—, —C(O)C(O)—, —S(O)—, —S(0)₂—,or —S(O)(NR⁷)—, wherein R⁷ is as defined above; Z is alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, —OR², or —N(R²)₂, wherein any carbon atom isoptionally substituted with J, wherein R² is as defined above; A² is abond or

R⁹ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and isoptionally substituted with 1-3 J groups; M is alkyl, cycloalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl,optionally substituted by 1-3 J groups, wherein any alkyl carbon atommay be replaced by a heteroatom; V is a bond, —CH₂—, —C(H)(R¹¹)—, -0-,—S—, or —N(R¹¹)—; R¹¹ is hydrogen or C₁₋₃ alkyl; K is a bond, -0-, —S—,—C(O)—, —S(O)—, —S(0)₂—, or —S(O)(NR¹¹)—, wherein R¹¹ is as definedabove; T is —R¹², -alkyl-R¹², -alkenyl-R¹², -alkynyl-R¹², —OR¹²,—N(R¹²)₂, —C(O)R¹², —C(═NOalkyl)R¹², or

R¹² is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl,cycloalkylidenyl, or heterocycloalkylidenyl, and is optionallysubstituted with 1-3 J groups, or a first R¹² and a second R¹², togetherwith the nitrogen to which they are bound, form a mono- or bicyclic ringsystem optionally substituted by 1-3 J groups; R¹⁰ is alkyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionallysubstituted with 1-3 hydrogens J groups; R¹⁵ is alkyl, cycloalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl,carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with1-3 J groups; and R¹⁶ is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl,or heterocyclyl; and z. z. Formula XXV

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinE represents CHO or B(OH)₂; R¹ represents lower alkyl, halo-lower alkyl,cyano-lower alkyl, lower alkylthio-lower alkyl, aryl-loweralkylthio-lower alkyl, aryl-lower alkyl, heteroaryllower alkyl, loweralkenyl or lower alkynyl; R² represents lower alkyl, hydroxy-loweralkyl, carboxylower alkyl, aryl-lower alkyl, aminocarbonyl-lower alkylor lower cycloalkyl-lower alkyl; and R³ represents hydrogen or loweralkyl; or R² and R³ together represent di- or trimethylene optionallysubstituted by hydroxy; R⁴ represents lower alkyl, hydroxy-lower alkyl,lower cycloalkyl-lower alkyl, carboxy-lower alkyl, aryllower alkyl,lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl,aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl or lowercycloalkyl; R⁵ represents lower alkyl, hydroxy-lower alkyl, loweralkylthio-lower alkyl, aryl-lower alkyl, aryl-lower alkylthio-loweralkyl, cyano-lower alkylthio-lower alkyl or lower cycloalkyl; R⁶represents hydrogen or lower alkyl; R⁷ represent lower alkyl,hydroxydower alkyl, carboxylower alkyl, aryl-iower alkyl, lowercycloalkyl-lower alkyl or lower cycloalkyl; R⁸ represents lower alkyl,hydroxy-lower alkyl, carboxylower alkyl or aryl-lower alkyl; and R⁹represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl,arylcarbonyl, lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonylor aryl-lower alkoxycarbonyl. z1. Formula XXVI:

or a pharmaceutically acceptable salt, solvate or ester thereof; whereinin Formula XXVI above B is an acyl derivative of formula R₁₁—C(O)—wherein R₁₁ is Cl-10 alkyl optionally substituted with carboxyl; or R₁₁is C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substituted with a C₁₋₆alkyl; a is 0 or 1; R₆, when present, is carboxy(lower)alkyl; b is 0 or1; R₅, when present, is C₁₋₆ alkyl, or carboxy(lower)alkyl; Y is H orC₁₋₆ alkyl; R₄ is C₁₋₁₀ alkyl; C₃₋₁₀ cycloalkyl; R₃ is C1-10 alkyl;C₃₋₁₀ cycloalkyl; W is a group of formula:

wherein R₂ is C₁₋₁₀ alkyl or C₃₋₇ cycloalkyl optionally substituted withcarboxyl; C₆ or C₁₀ aryl; or C₇₋₁₆ aralkyl; or W is a group of formula:

wherein X is CH or N; and R₂′ is C₃₋₄ alkylene that joins X to form a 5-or 6-membered ring, said ring optionally substituted with OH; SH; NH2;carboxyl; R₁₂; OR₁₂, SR₁₂, NHR₁₂ or NR₁₂R₁₂′ wherein R₁₂ and R₁₂′ areindependently: cyclic C₃₋₁₆ alkyl or acyclic C₁₋₁₆ alkyl or cyclic C₃₋₁₆alkenyl or acyclic C₂₋₁₆ alkenyl, said alkyl or alkenyl optionallysubstituted with NH₂, OH, SH, halo, or carboxyl; said alkyl or alkenyloptionally containing at least one heteroatom selected independentlyfrom the group consisting of: 0, S, and N; or R₁₂ and R₁₂′ areindependently C₆ or C₁₀ aryl or C₇₋₁₆ aralkyl optionally substitutedwith C₁₋₆alkyl, NH₂, OH, SH, halo, carboxyl or carboxy(lower)alkyl; saidaryl or aralkyl optionally containing at least one heteroatom selectedindependently from the group consisting of: 0, S, and N; said cyclicalkyl, cyclic alkenyl, aryl or aralkyl being optionally fused with asecond 5-, 6-, or 7-membered ring to form a cyclic system orheterocycle, said second ring being optionally substituted with NH₂. OH,SH, halo, carboxyl or carboxy(lower)alkyl; C₆ or C₁₀ aryl, orheterocycle; said second ring optionally containing at least oneheteroatom selected independently from the group consisting of: 0, S,and N; Q is a group of the formula:

wherein Z is CH; X is 0 or S; R₁ is H, C₁₋₆ alkyl or C₁₋₆ alkenyl bothoptionally substituted with thio or halo; and R₁₃ is C0-NH—R₁₄ whereinR₁₄ is hydrogen, cyclic C₃₋₁₀ alkyl or acyclic C₁₋₁₀ alkyl or cyclicC₃₋₁₀ alkenyl or acyclic C₂₋₁₀ alkenyl, said alkyl or alkenyl optionallysubstituted with NH₂, OH, SH, halo or carboxyl; said alkyl or alkenyloptionally containing at least one heteroatom selected independentlyfrom the group consisting of: 0, S, and N; or R₁₄ is C₆ or C₁₀ aryl orC₇₋₁₆ aralkyl optionally substituted with C₁₋₆ alkyl, NH₂, OH, SH, halo,carboxyl or carboxy(lower)alkyl or substituted with a further C₃₋₇cycloalkyl, C₆ or C₁₀ aryl, or heterocycle; said aryl or aralkyloptionally containing at least one heteroatom selected independentlyfrom the group consisting of: 0, S, and N; said cyclic alkyl, cyclicalkenyl, aryl or aralkyl being optionally fused with a second 5-, 6-, or7-membered ring to form a cyclic system or heterocycle, said second ringbeing optionally substituted with NH₂, OH, SH, halo, carboxyl orcarboxy(lower)alkyl or substituted with a further C₃₋₇ cycloalkyl, C₆ orC₁₀ aryl, or heterocycle; said second ring optionally containing atleast one heteroatom selected independently from the group consistingof: 0, S, and N; with the proviso that when Z is CH, then R₁₃ is not anα-amino acid or an ester thereof; Q is a phosphonate group of theformula:

wherein R₁₅ and R₁₆ are independently C₆₋₂₀ aryloxy; and R₁ is asdefined above.
 4. The method of any of claims 1, 2 or 3, whereincompound of Formulae I-XXVI is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate or ester thereof.
 5. Themethod of any of claims 1, 2 or 3, wherein compound is selected from thegroup consisting of:

and pharmaceutically acceptable salts or solvates thereof.
 6. The methodof any of claims 1, 2 or 3, wherein the compound is selected from thegroup consisting of:

and pharmaceutically acceptable salts or solvates thereof.
 7. The methodof any of claims 1, 2 or 3, wherein the at least one compound isadministered in one or more discrete dosages over twenty-four hours. 8.The method of claim 7, wherein the total amount of the at least onecompound administered over twenty-four hours is between 50 mg and 3,000mg.
 9. The method of claim 7, wherein the total amount of the at leastone compound administered over twenty-four hours is between 50 mg and2,400 mg.
 10. The method of any of claims 1, 2 or 3, wherein the totalamount of the at least one compound administered over twenty-four hoursis between 50 mg and 1,200 mg.
 11. The method of claim 7, wherein theone or more discrete dosages is between one and six doses overtwenty-four hours.
 12. The method of claim 7, wherein the one or morediscrete dosages is three or four doses in twenty-four hours.
 13. Themethod of claim 7, wherein the one or more discrete dosages are in oraldosage form.
 14. The method of claim 13, wherein the oral dosage form isselected from the group consisting of tablets, capsules, caplets,suspensions, emulsions, troches, lozenges, effervescent tablets,lollipops and reconstitutable powders.
 15. The method of any of claims1, 2 or 3, wherein the at least one compound is administered in oraldosage form and is administered concurrently with consumption of food.16. The method of any of claims 1, 2 or 3, wherein the at least onecompound is administered in oral dosage form and is administered up toninety minutes after consumption of food.
 17. The method of any ofclaims 1, 2 or 3, wherein the at least one compound is administered inoral dosage form and is administered up to thirty minutes before or upto thirty minutes after consumption of food.
 18. The method of any ofclaims 1, 2 or 3, wherein over 30% of the calories in the food are fromfat.
 19. The method of any of claims 1, 2 or 3, wherein the foodcontains at least 50 calories.
 20. The method of any of claims 1, 2 or3, wherein the food contains at least 100 calories.
 21. The method ofany of claims 1, 2 or 3, wherein the at least one compound isadministered in combination with at least one antiviral agent which isdifferent from the at least one compound and/or an immunomodulatoryagent.
 22. The method of claim 21, wherein the at least one compound isadministered in combination with a pharmaceutical selected from thegroup consisting of interferon alpha-2a, pegylated interferon alpha-2a,interferon alpha-2b pegylated interferon alpha-2b, interferonalphacon-1, and ribavirin.